Substituted quinolines as PDE-10 inhibitors

ABSTRACT

Provided herein are Cyclic Nucleotide Phosphodiesterase inhibitors, and pharmaceutical compositions thereof, useful for the treatment of, for example, central nervous system and metabolic diseases and disorder.

This application is a Divisional Application from U.S. patentapplication Ser. No. 13/700,051, filed Nov. 26, 2012, which is thenational stage entry of PCT/US2011/038057, filed May 26, 2011, whichclaims priority to U.S. Provisional Patent Application No. 61/348,683,filed May 26, 2010, and U.S. Provisional Patent Application No.61/411,410, filed Nov. 8, 2010, the contents of all of which are herebyincorporated herein by reference in their entireties.

I. FIELD

Provided herein are heteroaryl compounds useful for treating variousdisorders or diseases, such as disorders or diseases of the centralnervous system and metabolic disorders. Also provided herein arecompositions comprising the compounds, and methods of use thereof.

II. BACKGROUND

Central nervous system (CNS) disorders affect a wide range of thepopulation with differing severity. For example, schizophrenia is apsychopathic disorder of unknown origin, which usually appears for thefirst time in early adulthood and is marked by characteristics, such as,psychotic symptoms, phasic progression and development, anddeterioration in social behavior and professional capability.Characteristic psychotic symptoms include disorders of thought content(e.g., multiple, fragmentary, incoherent, implausible or simplydelusional contents, or ideas of persecution) and of mentality (e.g.,loss of association, flight of imagination, incoherence, orincomprehensibility), as well as disorders of perceptibility (e.g.,hallucinations), emotions (e.g., superficial or inadequate emotions),self-perceptions, intentions, impulses, and inter-human relationships,and psychomotoric disorders (e.g., catatonia). Other symptoms are alsoassociated with this disorder. See, e.g., Diagnostic and StatisticalManual of Mental Disorders, 4^(th) Ed., American Psychiatric Association(1997) (DSM-IV™).

Schizophrenia can be classified into various subgroups. For example, theparanoid type is characterized by delusions and hallucinations andabsence of thought disorder, disorganized behavior, and affectiveflattening. The disorganized type, also named hebephrenic schizophrenia,is characterized by the presence of both thought disorder and affectiveflattening. The cataconic type is characterized by prominent psychomotordisturbances, including symptoms of catatonic stupor and waxyflexibility. In the undifferentiated type, psychotic symptoms arepresent but the criteria for paranoid, disorganized, or catatonic typeshave not been met.

The symptoms of schizophrenia normally manifest themselves in threebroad categories, i.e., positive, negative and cognitive symptoms.Positive symptoms are those that represent an excess of normalexperiences, such as hallucinations, disorganized speech, and delusions.Negative symptoms are those where the patient suffers from a lack ofnormal experiences, such as anhedonia, lack of motivation, inability toexperience pleasure, and lack of social interaction. The cognitivesymptoms relate to cognitive impairment in schizophrenics, such as lackof sustained attention, impairment of memory, and deficits in decisionmaking. The current anti-psychotics are somewhat effective in treatingthe positive symptoms but are less effective in treating the negative orcognitive symptoms. For instance, the current typical or atypicalanti-psychotics do not address cognitive or negative symptoms ofschizophrenia, and only treat the positive symptoms in approximately 40%of patients.

Cognitive impairments include a decline in cognitive functions orcognitive domains, e.g., working memory, attention and vigilance, verballearning and memory, visual learning and memory, reasoning and problemsolving, e.g., executive function, speed of processing and/or socialcognition. In particular, cognitive impairment may indicate deficits inattention, disorganized thinking, slow thinking, difficulty inunderstanding, poor concentration, impairment of problem solving, poormemory, difficulties in expressing thoughts, difficulties in integratingthoughts, feelings and behavior, or difficulties in extinction ofirrelevant thoughts.

Agitation is a well-recognized behavioral disorder with a range ofsymptoms, including hostility, extreme excitement, poor impulse control,tension, and uncooperativeness. Agitation is common in the elderly andoften associated with dementia such as those caused by Alzheimer'sdisease, Parkinson's disease, and Huntington's disease, and by diseasesthat affect blood vessels, such as stroke or multi-infarct dementia,which is caused by multiple strokes in the brain. An estimated fivepercent of people aged 65 and older and up to 20 percent of those aged80 and older are affected by dementia. Of these sufferers, nearly halfexhibit behavioral disturbances, such as agitation, wandering, andviolent outbursts. Agitated behaviors can also be manifested incognitively intact elderly people and by those with psychiatricdisorders other than dementia.

Dementia is characterized by several cognitive impairments includingsignificant memory deficit and can stand alone, or be an underlyingcharacteristic feature of a variety of diseases, including but notlimited to, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, and multiple sclerosis.

Thus, there remains a great need for effective treatments of various CNSdisorders.

Cyclic nucleotide phosphodiesterases (PDEs) are a super family ofenzymes encoded by twenty-one genes, and are subdivided into elevenknown families based on structure and function. PDEs are modular enzymeshaving a catalytic domain in the C-terminal portion of the protein andregulatory elements in the N-terminal portion. PDEs hydrolyze thephosphodiester bond of cyclic nucleotides, e.g., cyclic adenosinemonophosphate (cAMP) and cyclic guanosine monophosphate (cGMP),converting them into the corresponding monophosphates. cAMP and cGMPfunction as intracellular second messengers regulating a wide range ofintracellular processes. For instance, in neurons cAMP and cGMP activatecyclic-nucleotide-dependent kinases and the subsequent phosphorylationof proteins involved in acute regulation of synaptic transmission and inneuronal differentiation and survival. PDEs are therefore importantregulators of a wide variety of physiological processes. PDEs areexpressed differentially throughout the organism and cyclic nucleotidesignaling is highly compartmentalized within individual cells. Thus,different PDE isozymes can serve distinct physiological functions.Compounds that can selectively inhibit distinct PDE families or isozymesmay offer additional therapeutic benefits, fewer side effects, or both.

PDE-10 was first reported in 1999 (Soderling et al., Proc. Natl. Acad.Sci., 1999, 96, 7071-76; Loughney et al., Gene, 1999, 234, 109-17;Fujishige et al., J. Biol. Chem., 1999, 274, 18438-45). Homologyscreening revealed mouse PDE-10A as the first member of the PDE-10family of enzymes. The human PDE-10 sequence is highly homologous toboth the rat and mouse PDE-10 enzymes. The PDE-10 family of enzymes hasa lower degree of sequence homology as compared to previously identifiedPDE families. PDE-10 can hydrolyze both cAMP (K_(m)=0.26 μM) and cGMP(K_(m)=7.2 μM), and has a five-fold greater V_(max) for cGMP than forcAMP.

PDE-10A is primarily expressed in the brain, also found in testes.PDE-10A mRNA and protein are abundant in brain tissues, and are mainlydetected at high levels in the medium spiny neurons (MSN) of thestriatum, a distribution conserved across mammalian species. Thestriatal MSNs provide input to the basal ganglia circuit, affectingaction selection and execution, and suppressing undesired responses tosensory stimuli. PDE-10A has become an emerging target for thedevelopment of new anti-psychotics. Inhibitors of PDE-10A have beenshown to increase cAMP and cGMP levels in striatal tissue and havedemonstrated efficacy against not only positive but also negative andcognitive symptoms of schizophrenia in animals. PDE-10A is also usefulin treating metabolic disorders, such as diabetes, obesity, andmetabolic syndrome.

Citation of any references in this Section of the application is not tobe construed as an admission that such reference is prior art to thepresent application.

III. SUMMARY

Provided herein are compounds of formula (I), or pharmaceuticallyacceptable salts or stereoisomers thereof:A-L-B   (I),wherein A, L, and B are defined herein elsewhere. The compounds areuseful for treating various diseases or disorders, such as CNS disordersand metabolic disorders.

Also provided herein are compositions and dosage forms comprising, acompound provided herein, and one or more pharmaceutically acceptableexcipient(s). Compositions and dosage forms provided herein may furthercomprise one or more additional active ingredients.

Also provided herein are methods for the treatment, prevention, and/ormanagement of various disorders, such as a CNS disorder or a metabolicdisorder, e.g., the treatment, prevention, and/or amelioration of one ormore symptoms of a disorder, using the compounds and compositionsprovided herein. In one embodiment, the disorders provided hereininclude, but are not limited to, schizophrenia, psychosis, cognitivedisorders, mood disorders, attention deficit disorders, andneurodegenerative diseases. In one embodiment, the disorders include,but are not limited to, neurological disorder, schizophrenia,schizophrenia-related disorder, schizophrenia spectrum disorder, acuteschizophrenia, chronic schizophrenia, NOS schizophrenia, schizoaffectivedisorder, schizophreniform disorder, paraphrenia, paranoid personalitydisorder, schizoid personality disorder, schizotypal personalitydisorder, delusional disorder, psychosis, disease having a psychosiscomponent, psychotic disorder, brief psychotic disorder, Alzheimer'spsychosis, Parkinson's psychosis, shared psychotic disorder,substance-induced psychotic disorder (e.g., cocaine, alcohol,amphetamine), psychotic disorder due to a general medical condition,psychoaffective disorder, aggression, delirium, excitative psychosis,Tourette's syndrome, manic disorder, organic psychosis, NOS psychosis,convulsion, seizure, agitation, posttraumatic stress disorder, behaviordisorder, neurodegenerative disease, Huntington's disease, Alzheimer'sdisease, Parkinson's disease, dyskinesia, dementia, mood disorder,bipolar disorder, anxiety, depression, major depressive disorder,unipolar depression, treatment resistant depression, dysthymia,affective disorder, seasonal affective disorder, obsessive-compulsivedisorder, attention deficit disorder (ADD), attention deficithyperactivity disorder (ADHD), vertigo, pain, neuropathic pain,sensitization accompanying neuropathic pain, inflammatory pain,fibromyalgia, migraine, cognitive impairment, cognitive impairmentassociated with schizophrenia, cognitive deficit in Alzheimer's disease,cognitive deficit in Parkinson's disease, movement disorder, restlessleg syndrome (RLS), multiple sclerosis, sleep disorder, substance abuseor dependency (e.g., nicotine, cocaine), addiction, eating disorder,autism, obesity, undesirable weight retention or weight gain, metabolicsyndrome, diabetes, non-insulin dependent diabetes, impaired glucosetolerance, and hyperglycemia.

In one embodiment, provided herein is a method of treating, preventing,and/or managing schizophrenia or related disorders, including but notlimited to, schizoaffective disorder, schizophreniform disorder,paraphrenia, paranoid personality disorder, schizoid personalitydisorder, and schizotypal personality disorder; a disease having apsychosis component, including but not limited to, Alzheimer'spsychosis, Parkinson's psychosis, shared psychotic disorder, andsubstance-induced psychotic disorder; cognitive impairment, includingbut not limited to, cognitive impairment associated with schizophrenia,cognitive deficit in Alzheimer's disease, and cognitive deficit inParkinson's disease; mood disorder, including but not limited to,bipolar disorder; attention deficit disorder, including but not limitedto attention deficit hyperactive disorder; neurodegcnerative disease,including but not limited to, Huntington's disease; or depression,including but not limited to, major depressive disorder, unipolardepression, and treatment resistant depression. In one embodiment,provided herein is a method of treating, preventing, and/or managing adisorder provided herein elsewhere (e.g., a CNS disorder or a metabolicdisorder), in a subject, such as a mammal, e.g., human, rodent (e.g.,mice and rats), cat, dog, and non-human primate, among others. In oneembodiment, provided herein is a method of treating, preventing, and/orameliorating one or more symptoms associated with a disorder providedherein elsewhere (e.g., a CNS disorder or a metabolic disorder), in asubject, such as a mammal, e.g., human, rodent (e.g., mice and rats),cat, dog, and non-human primate, among others. In one embodiment, themethod comprises contacting a compound provided herein with a PDEenzyme. In one embodiment, the method comprises contacting a compoundprovided herein with a PDE enzyme expressed in the central nervoussystem. In one embodiment, the method comprises contacting a compoundprovided herein with PDE-10A. In one embodiment, the method comprisescontacting a cell with a compound provided herein. In an exemplaryembodiment, the cell is a brain cell, such as, e.g., a MSN cell, aneuronal cell, or a glial cell.

IV. DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood by one of ordinaryskill in the art. All publications and patents referred to herein areincorporated by reference herein in their entireties.

A. Definitions

As used in the specification and the accompanying claims, the indefinitearticles “a” and “an” and the definite article “the” include plural aswell as singular referents, unless the context clearly dictatesotherwise.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a linear or branched saturated monovalent hydrocarbon radical,wherein the alkyl may be optionally substituted with one or moresubstituents. In certain embodiments, the alkyl is a linear saturatedmonovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 12 (C₁₋₁₂), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbonatoms, or branched saturated monovalent hydrocarbon radical of 3 to 20(C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6(C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ and branched C₃₋₆ alkylgroups are also referred as “lower alkyl.” Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl (including allisomeric forms, e.g., n-propyl, isopropyl), butyl (including allisomeric forms, e.g., n-butyl, isobutyl, i-butyl), pentyl (including allisomeric forms), and hexyl (including all isomeric forms). For example,C₁₋₆ alkyl refers to a linear saturated monovalent hydrocarbon radicalof 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbonradical of 3 to 6 carbon atoms. In certain embodiments, the alkyl isoptionally substituted as described herein elsewhere. In someembodiments, the alkyl is optionally substituted with one or more halo.

As used herein, and unless otherwise specified, the term “alkenyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbondouble bonds. The alkenyl may be optionally substituted with one or moresubstituents. The term “alkenyl” also encompasses radicals having “cis”and “trans” configurations, or alternatively, “E” and “Z”configurations, as appreciated by those of ordinary skill in the art.For example, C₂₋₆ alkenyl refers to a linear unsaturated monovalenthydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturatedmonovalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12 (C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2to 6 (C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radicalof 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀),or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groups include, butare not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl,and 4-methylbutenyl. In certain embodiments, the alkenyl is optionallysubstituted as described herein elsewhere. In some embodiments, thealkenyl is optionally substituted with one or more halo.

As used herein, and unless otherwise specified, the term “alkynyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbontriple bonds. The alkynyl may be optionally substituted with one or moresubstituents. In certain embodiments, the alkynyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12(C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkynyl groups include, but are not limited to, ethynyl (—C≡CH) andpropargyl (—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to a linearunsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkynyl is optionally substituted asdescribed herein elsewhere. In some embodiments, the alkynyl isoptionally substituted with one or more halo.

As used herein, and unless otherwise specified, the term “cycloalkyl”refers to a cyclic fully or partially saturated bridged and/ornon-bridged hydrocarbon radical or ring system, which may be optionallysubstituted with one or more substituents. In certain embodiments, thecycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 12(C₃₋₁₂), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl,cyclohexenyl, cycloheptyl, decalinyl, and adamantyl. In certainembodiments, the cycloalkyl is optionally substituted as describedherein elsewhere. In some embodiments, the cycloalkyl is optionallysubstituted with one or more halo.

As used herein, and unless otherwise specified, the term “heteroalkyl”refers to a stable straight or branched chain consisting of the statednumber of carbon atoms and from one or more, in one embodiment, one tothree, heteroatoms selected from the group consisting of O, N, Si, andS, and wherein the nitrogen and sulfur atoms are optionally oxidized andthe nitrogen heteroatom can optionally be quaternized. In oneembodiment, the heteroatom(s) O and N can be placed at any interiorposition of the heteroalkyl group. In one embodiment, the heteroatom(s)S and Si can be placed at any position of the heteroalkyl group (e.g.,interior or terminal position), including the position at which thealkyl group is attached to the remainder of the molecule. Examplesinclude, but are not limited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms can be consecutive, such as,for example, —CH₂—NH—O—CH₃ and —CH₂—O—Si(CH₃)₃. In certain embodiments,the heteroalkyl is optionally substituted as described herein elsewhere.In some embodiments, the heteroalkyl is optionally substituted with oneor more halo.

As used herein, and unless otherwise specified, the term “alkoxyl” or“alkoxy” refers to a stable straight or branched chain, or cyclichydrocarbon radical, or combinations thereof, consisting of the statednumber of carbon atoms and from one or more, in one embodiment, one tothree, O atoms, wherein at least one O atom is at the position where thealkoxyl or alkoxy group is attached to the remainder of the molecule.Examples of alkoxyl include, but are not limited to, —O—CH₃, —O—CF₃,—O—CH₂—CH₃, —O—CH₂—CH₂—CH₃, —O—CH—(CH₃)₂, and —O—CH₂—CH₂—O—CH₃. In oneembodiment, the alkoxyl is optionally substituted as described hereinelsewhere. In some embodiments, the alkoxyl is optionally substitutedwith one or more halo.

As used herein, and unless otherwise specified, the term “aminoalkyl” or“alkylamino” refers to a stable straight or branched chain, or cyclichydrocarbon radical, or combinations thereof, consisting of the statednumber of carbon atoms and from one or more, in one embodiment, one tothree, N atoms, wherein at least one N atom is at the position where theaminoalkyl or alkylamino group is attached to the remainder of themolecule. Examples of aminoalkyl include, but are not limited to,—NH—CH₃, —N(CH₃)₂, —NH—CH₂—CH₃, —N(CH₃)—CH₂—CH₃, —NH—CH—(CH₃)₂,—NH—CH₂—CH₂—NH—CH₃, and —NH—CH₂—CH₂—N(CH₃)₂. In one embodiment, theaminoalkyl is optionally substituted as described herein elsewhere. Insome embodiments, the aminoalkyl is optionally substituted with one ormore halo.

As used herein, and unless otherwise specified, the term “aryl” refersto an optionally substituted monocyclic or multicyclic radical or ringsystem that contains at least one aromatic hydrocarbon ring. In certainembodiments, the aryl has from 6 to 20, from 6 to 15, or from 6 to 10ring atoms. Examples of aryl groups include, but are not limited to,phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl,biphenyl, and terphenyl. In certain embodiments, aryl also refers tobicyclic, tricyclic, or tetracyclic carbon rings, where one of the ringsis aromatic and the other(s) of the rings may be saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl (tetralinyl). In certain embodiments,aryl may be a bicyclic, tricyclic, or tetracyclic ring system, where atleast one of the rings is aromatic and one or more of the ring(s) may besaturated or partially unsaturated optionally containing one or moreheteroatoms independently selected from O, S, and N. In certainembodiments, the aryl is optionally substituted with one or moresubstituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term “arylalkyl” or“aralkyl” refers to a monovalent alkyl group substituted with aryl. Anexample of aralkyl includes, but is not limited to, benzyl. In certainembodiments, both alkyl and aryl may be optionally substituted with oneor more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term“heteroarylalkyl” or “heteroaralkyl” refers to a monovalent alkyl groupsubstituted with heteroaryl. In certain embodiments, both alkyl andheteroaryl may be optionally substituted with one or more substituentsas described herein elsewhere.

As used herein, and unless otherwise specified, the term “heteroaryl”refers to an optionally substituted monocyclic or multicyclic radical orring system which contains at least one aromatic ring having one or moreheteroatoms independently selected from O, S, and N. In one embodiment,each ring of a heteroaryl group can contain one or two O atoms, one ortwo S atoms, and/or one to four N atoms, provided that the total numberof heteroatoms in each ring is four or less and each ring contains atleast one carbon atom. In certain embodiments, the heteroaryl has from 5to 20, from 5 to 15, or from 5 to 10 ring atoms. In certain embodiments,heteroaryl also refers to bicyclic, tricyclic, or tetracyclic rings,where one of the rings is aromatic having one or more heteroatomsindependently selected from O, S, and N, and the other(s) of the ringsmay be saturated, partially unsaturated, or aromatic and may becarbocyclic or contain one or more heteroatoms independently selectedfrom O, S, and N. Examples of monocyclic heteroaryl groups include, butare not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl,triazinyl, and triazolyl. Examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, bcnzopyranyl, bcnzothiadiazolyl, bcnzothiazolyl,bcnzothicnyl, bcnzotriazolyl, bcnzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, theheteroaryl is optionally substituted with one or more substituents asdescribed herein elsewhere.

As used herein, and unless otherwise specified, the term“heterocycloalkyl” or “heterocyclyl” refers to an optionally substitutedmonocyclic or multicyclic radical or ring system which contains at leastone non-aromatic saturated or partially saturated ring having one ormore heteroatoms independently selected from O, S, and N. In certainembodiments, the heterocyclyl or heterocycloalkyl group has from 3 to20, from 3 to 15, from 3 to 10, from 3 to 8, from 4 to 7, or from 5 to 6ring atoms. In certain embodiments, the heterocyclyl or heterocycloalkylis a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, whichmay include a fused or bridged ring system, and in which the nitrogen orsulfur atoms may be optionally oxidized, the nitrogen atoms may beoptionally quaternized, the ring carbon atoms may be optionallysubstituted with oxo, and some rings may be partially or fullysaturated, or aromatic. The heterocycloalkyl or heterocyclyl may beattached to the main structure at a heteroatom or a carbon atom whichresults in the creation of a stable compound. Examples include, but arenot limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl,benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, bcnzothiopyranyl, bcnzoxazinyl, β-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, when the heterocyclyl orheterocycloalkyl ring contains one or more O, the heterocyclyl orheterocycloalkyl may also be referred to as “cycloalkoxyl.” In certainembodiments, the heterocyclyl or heterocycloalkyl is optionallysubstituted with one or more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term “halogen”,“halide” or “halo” refers to fluorine, chlorine, bromine, and iodine.

As used herein, and unless otherwise specified, the term “hydrogen”encompasses proton (¹H), deuterium (²H), tritium (³H), and/or mixturesthereof. In a compound described herein, one or more positions occupiedby hydrogen may be enriched with deuterium and/or tritium. Suchisotopically enriched analogs may be prepared from suitable isotopicallylabeled starting material obtained from a commercial source or preparedusing known literature procedures.

As used herein, and unless otherwise specified, the term “optionallysubstituted” is intended to mean that a group, such as an alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, alkoxyl, aminoalkyl, aryl,aralkyl, heteroaralkyl, heteroaryl, or heterocyclyl, may be substitutedwith one or more substituents independently selected from, e.g., (a)C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl,C₇₋₁₅ aralkyl, heteroaryl, and heterocyclyl, each optionally substitutedwith one or more, in one embodiment, one, two, three, or four,substituents Q¹; and (b) halo, cyano (—CN), nitro (—NO₂), oxo (═O),—C(O)R^(a), —C(O)OR^(a), —C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c),—OR^(a), —OC(O)R^(a), —OC(O)OR^(a), —OC(O)NR^(b)R^(c),—OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a), —OS(O)₂R^(a), —OS(O)NR^(b)R^(c),—OS(O)₂NR^(b)R^(c), —NR^(b)R^(c), —NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d),—NR^(a)C(O)NR^(b)R^(c), —NR^(a)C(═NR^(d))NR^(b)R^(c), —NR^(a)S(O)R^(d),—NR^(a)S(O)₂R^(d), —NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c),—SR^(a), —S(O)R^(a), —S(O)₂R^(a), —S(O)NR^(b)R^(c), and—S(O)₂NR^(b)R^(c), wherein each R^(a), R^(b), R^(c), and R^(d) isindependently (i) hydrogen; (ii) C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl, heteroaryl, or heterocyclyl,each optionally substituted with one or more, in one embodiment, one,two, three, or four, substituents Q¹; or (iii) R^(b) and R^(c) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl, optionally substituted with one or more, in oneembodiment, one, two, three, or four, substituents Q¹. As used herein,all groups that can be substituted are “optionally substituted,” unlessotherwise specified.

In one embodiment, each Q¹ is independently selected from the groupconsisting of (a) cyano, halo, oxo, and nitro; and (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(c))NR^(f)R^(g), —OR^(c), —OC(O)R^(c),—OC(O)OR^(c), —OC(O)NR^(f)R^(g), —OC(═NR)NR^(f)R^(g), —OS(O)R^(c),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(g),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), SR^(e), S(O)R^(e),S(O)₂R^(e), S(O)NR^(f)R^(g), and S(O)₂NR^(f)R^(g); wherein each R^(e),R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) together with theN atom to which they are attached form heteroaryl or heterocyclyl.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids; or from pharmaceutically acceptable non-toxic bases,including inorganic bases and organic bases. In one embodiment, suitablenon-toxic acids include, but are not limited to, acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic,galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic.

As used herein, and unless otherwise specified, the term “solvate”refers to a compound provided herein or a salt thereof, which furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stercomerically pure andenantiomerically/stercomerically enriched compounds provided herein.

As used herein and unless otherwise specified, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stercoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,or greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound.

As used herein and unless otherwise indicated, the term “stercomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

In certain embodiments, as used herein, and unless otherwise specified,“optically active” and “enantiomerically active” refer to a collectionof molecules, which has an enantiomeric excess of no less than about50%, no less than about 70%, no less than about 80%, no less than about90%, no less than about 91%, no less than about 92%, no less than about93%, no less than about 94%, no less than about 95%, no less than about96%, no less than about 97%, no less than about 98%, no less than about99%, no less than about 99.5%, or no less than about 99.8%. In certainembodiments, the compound comprises about 95% or more of the desiredenantiomer and about 5% or less of the less preferred enantiomer basedon the total weight of the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

As used herein, and unless otherwise indicated, the term “about” or“approximately” means an acceptable error for a particular value asdetermined by one of ordinary skill in the art, which depends in part onhow the value is measured or determined. In certain embodiments, theterm “about” or “approximately” means within 1, 2, 3, or 4 standarddeviations. In certain embodiments, the term “about” or “approximately”means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%,0.5%, or 0.05% of a given value or range.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable carrier,” “pharmaceutically acceptableexcipient,” “physiologically acceptable carrier,” or “physiologicallyacceptable excipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. In one embodiment, each component is“pharmaceutically acceptable” in the sense of being compatible with theother ingredients of a pharmaceutical formulation, and suitable for usein contact with the tissue or organ of humans and animals withoutexcessive toxicity, irritation, allergic response, immunogenicity, orother problems or complications, commensurate with a reasonablebenefit/risk ratio. See, Remington: The Science and Practice ofPharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia,Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe etal., Eds., The Pharmaceutical Press and the American PharmaceuticalAssociation: 2005; and Handbook of Pharmaceutical Additives, 3rdEdition, Ash and Ash Eds., Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed.,CRC Press LLC: Boca Raton, Fla., 2009.

As used herein, and unless otherwise specified, the terms “activeingredient” and “active substance” refer to a compound, which isadministered, alone or in combination with one or more pharmaceuticallyacceptable excipients, to a subject for treating, preventing, orameliorating one or more symptoms of a condition, disorder, or disease.As used herein, “active ingredient” and “active substance” may be anoptically active isomer of a compound described herein.

As used herein, and unless otherwise specified, the terms “drug” and“therapeutic agent” refer to a compound, or a pharmaceutical compositionthereof, which is administered to a subject for treating, preventing,managing, or ameliorating one or more symptoms of a condition, disorder,or disease.

As used herein, and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of the particular disease.

As used herein, and unless otherwise indicated, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. In certain embodiments, the terms refer to thetreatment with or administration of a compound provided herein, with orwithout other additional active compound, prior to the onset ofsymptoms, particularly to patients at risk of disease or disordersprovided herein. The terms encompass the inhibition or reduction of asymptom of the particular disease. Patients with familial history of adisease in particular are candidates for preventive regimens in certainembodiments. In addition, patients who have a history of recurringsymptoms are also potential candidates for the prevention. In thisregard, the term “prevention” may be interchangeably used with the term“prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing,” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. Often, the beneficial effects that a subjectderives from a prophylactic and/or therapeutic agent do not result in acure of the disease or disorder. In this regard, the term “managing”encompasses treating a patient who had suffered from the particulardisease in an attempt to prevent or minimize the recurrence of thedisease.

As used herein, and unless otherwise specified, “amelioration” of thesymptoms of a particular disorder by administration of a particularpharmaceutical composition refers to any lessening, whether permanent ortemporary, lasting or transient, that can be attributed to or associatedwith the administration of the composition.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

As used herein, and unless otherwise specified, the term “subject” isdefined herein to include animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In specific embodiments, thesubject is a human.

As used herein, and unless otherwise specified, the term “neurologicaldisorder” refers to any condition of the central or peripheral nervoussystem of a mammal. The term “neurological disorder” includes, but isnot limited to, neurodegenerative diseases (e.g., Alzheimer's disease,Parkinson's disease and amyotrophic lateral sclerosis), neuropsychiatricdiseases (e.g., schizophrenia and anxieties, such as general anxietydisorder), and affective disorders (e.g., depression and attentiondeficit disorder). Exemplary neurological disorders include, but are notlimited to, MLS (cerebellar ataxia), Huntington's disease, Downsyndrome, multi-infarct dementia, depression (e.g., major depressivedisorder, dysthymia, and bipolar depressive disorder), dementias,movement disorders, psychoses, alcoholism, post-traumatic stressdisorder and the like. “Neurological disorder” also includes anycondition associated with the disorder. For instance, a method oftreating a neurodegenerative disorder includes methods of treating lossof memory and/or loss of cognition associated with a neurodegenerativedisorder. An exemplary method would also include treating or preventingloss of neuronal function characteristic of neurodegenerative disorder.

As used herein, and unless otherwise specified, the terms “psychosis,”“schizophrenia,” “obsessive-compulsive disorder,” “substance abuse,”“anxiety,” “eating disorders,” “migraine,” and other CNS disordersdescribed herein elsewhere are used herein in a manner consistent withtheir accepted meanings in the art. See, e.g., Diagnostic andStatistical Manual of Mental Disorders, 4^(th) Ed., American PsychiatricAssociation (1997) (DSM-IV™). As used herein, and unless otherwisespecified, the term “affective disorder” includes depression, attentiondeficit disorder, attention deficit disorder with hyperactivity, bipolarand manic conditions, and the like. The terms “attention deficitdisorder” (ADD) and “attention deficit disorder with hyperactivity”(ADDH), or attention deficit/hyperactivity disorder (AD/HD), are usedherein in accordance with the accepted meanings as found in theDiagnostic and Statistical Manual of Mental Disorders, 4^(th) Ed.,American Psychiatric Association (1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “depression”includes all forms of depression including, but not limited to, majordepressive disorder (MDD), bipolar disorder, seasonal affective disorder(SAD), dysthymia, and treatment resistant depression. “Major depressivedisorder” is used herein interchangeably with “unipolar depression” and“major depression.” “Depression” may also include any condition commonlyassociated with depression, such as all forms of fatigue (e.g., chronicfatigue syndrome) and cognitive deficits.

As used herein, and unless otherwise specified, the term “pain” refersto an unpleasant sensory and emotional experience. The term “pain,” asused herein, refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic peripheral neuropathic pain (See, e.g.,Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al.,eds., 12th ed. 1991); Williams et al., J. of Med. Chem. 42: 1481-1485(1999), herein each incorporated by reference in their entirety). “Pain”is also meant to include mixed etiology pain, dual mechanism pain,allodynia, causalgia, central pain, hyperesthesia, hyperpathia,dysesthesia, and hyperalgesia. In addition, The term “pain” includespain resulting from dysfunction of the nervous system: organic painstates that share clinical features of neuropathic pain and possiblecommon pathophysiology mechanisms, but are not initiated by anidentifiable lesion in any part of the nervous system.

As used herein, and unless otherwise specified, the term “fibromyalgia”refers to a chronic condition characterized by diffuse or specificmuscle, joint, or bone pain, along with fatigue and a range of othersymptoms. Previously, fibromyalgia was known by other names such asfibrositis, chronic muscle pain syndrome, psychogenic rheumatism andtension myalgias.

As used herein, and unless otherwise specified, the terms “overweight”and “obese” refer to adult persons 18 years or older having a greaterthan ideal body weight (e.g., greater than ideal body fat) that can bemeasured by the body mass index (BMI), which is generally correlatedwith total body fat and the relative risk of suffering from prematuredeath or disability due to diseases as a consequence of the overweightor obese condition. BMI is calculated by weight in kilograms divided byheight in meters squared (kg/m²), or alternatively by weight in pounds,multiplied by 703, divided by height in inches squared (lbs×703/in²).Overweight individuals typically have a BMI of between about 25 andabout 29, whereas obese individuals typically have a BMI of about 30 ormore (see, e.g., National Heart, Lung, and Blood Institute, ClinicalGuidelines on the Identification, Evaluation, and Treatment ofOverweight and Obesity in Adults, The Evidence Report, Washington, D.C.,U.S. Department of Health and Human Services, NIII publication no.98-4083, 1998). Other means for indicating excess body weight, excessbody fat, and obesity include direct measure of body fat and/orwaist-to-hip ratio measurements.

As used herein, and unless otherwise specified, the term “metabolicsyndrome” is used according to its usual meaning in the art. TheAmerican Heart Association characterizes metabolic syndrome as having atleast three or more of the following symptoms: 1) elevated waistcircumference [>102 cm (40 inches) in men; >88 cm (35 inches) in women];2) elevated triglycerides [≧150 mg/dL (>1.695 mmol/L) or drug treatmentfor elevated triglycerides]; 3) reduced HDL cholesterol [<40 mg/dL(1.036 mmol/L) in men; <50 mg/dL (1.295 mmol/L) in women; or drugtreatment for reduced IIDL-C]; 4) elevated blood pressure [≧130/85 mmIIgor drug treatment for hypertension]; and 5) elevated fasting glucose[≧110 mg/dL or drug treatment for elevated glucose]. According to theWorld Health Organization, metabolic syndrome includes individualssuffering from diabetes, impaired glucose tolerance, impaired fastingglucose, or insulin resistance plus two or more of the followingsymptoms: 1) high blood pressure [≧160/90 mmHg]; 2) hyperlipdemia[triglyceride concentration ≧150 mg/dL (1.695 mmol/L) and/or IIDLcholesterol <35 mg/dL (0.9 mmol/L) in men and <39 mg/dL (1.0 mmol/L) inwomen]; 3) central obesity [waist-to-hip ratio of >0.90 for menand >0.85 for women and/or BMI>30 kg/m²]; and 4) microalbuminuria[urinary albumin excretion rate ≧20 μg/min or an albumin-to-creatinineratio ≧20 mg/kg).

B. Compounds

In one embodiment, provided herein is a compound of formula (I):A-L-B   (I),or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

L is —C(R⁶)₂—C(R⁶)₂—, —C(R⁶)═C(R⁶)—, —N(R¹⁰)—C(R⁶)₂—, —O—C(R⁶)₂—,—C(R⁶)₂—N(R¹⁰)—, —C(R⁶)₂—O—, —C(R⁶)₂—S—, —S—, —(CH₂)_(p)—S—(CH₂)_(q)—,or —(CH₂)_(u)—;

A is

B is

A¹-A²- is —NR⁷—C(═O)—, —C(═O)—NR⁷—, —O—C(═O)—, —C(═O)—O—, —N═CR⁸—,—CR⁸═N—, —CR⁸═CR⁸—, or —N═N—;

A³ is N or CR⁹

A⁴ is NR⁵, O, or S;

A⁵ is CR⁵ or N;

A⁶ is N or CR⁵;

R¹ and R² are each independently (i) hydrogen, cyano, or halo; or (ii)(C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₁-C₁₀)alkoxyl, (C₁-C₁₀)aminoalkyl,(C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10 membered)aryl, (5 to10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxyl, amino,imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which isoptionally substituted with one or more R¹¹; or (iii) R¹ and R² togetherwith the carbon atoms to which they are attached form a ring optionallysubstituted with one or more R¹¹;

R³ and R⁴ are each independently (i) hydrogen, cyano, or halo; or (ii)(C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₁-C₁₀)alkoxyl, (C₁-C₁₀)aminoalkyl,(C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10 membered)aryl, (5 to10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxyl, amino,imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which isoptionally substituted with one or more R¹¹; or (iii) R³ and R⁴ togetherwith the atoms to which they are attached form a ring optionallysubstituted with one or more R¹¹;

R⁵ is (i) hydrogen, cyano, or halo; or (ii) (C₁-C₁₀)alkyl,(C₂-C₁₀)alkenyl, (C₁-C₁₀)alkoxyl, (C₁-C₁₀)aminoalkyl,(C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10 membered)aryl, (5 to10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxyl, amino,imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which isoptionally substituted with one or more R; or (iii) R⁴ and R⁵ togetherwith the atoms to which they are attached form a ring optionallysubstituted with one or more R¹¹;

R¹⁹ is (i) hydrogen, cyano, or halo; or (ii) (C₁-C₁₀)alkyl,(C₂-C₁₀)alkenyl, (C₁-C₁₀)alkoxyl, (C₁-C₁₀)aminoalkyl,(C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10 membered)aryl, (5 to10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxyl, amino,imino, amido, carbonyl, thiol, sulfinyl, or sulfonyl, each of which isoptionally substituted with one or more R¹¹;

R²⁰ is (i) hydrogen; or (ii) (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl,(C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10 membered)aryl, (5 to10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, carbonyl, orsulfonyl, each of which is optionally substituted with one or more R¹¹;

each occurrence of R⁶ is independently hydrogen, halo, or (C₁-C₆)alkyloptionally substituted with one or more halo;

R⁷ is hydrogen or (C₁-C₆)alkyl optionally substituted with one or morehalo; each occurrence of R¹¹ is independently (i) hydrogen, cyano, orhalo; or (ii) (C₁-C₁₀) alkyl, (C₂-C₁₀)alkenyl, (C₁-C₁₀)alkoxyl,(C₁-C₁₀)aminoalkyl, (C₁-C₁₀)heteroalkyl, (C₃-C₁₀) cycloalkyl, (6 to 10membered)aryl, (5 to 10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxyl, amino, imino, amido, carbonyl, thiol, sulfinyl,or sulfonyl, each of which is optionally substituted with one or moreR¹¹;

R⁹ is hydrogen, cyano, halo, (C₁-C₆)alkyl optionally substituted withone or more halo, or (C₁-C₆)alkoxyl optionally substituted with one ormore halo;

R¹⁰ is hydrogen or (C₁-C₆)alkyl optionally substituted with one or morehalo;

each occurrence of R¹¹ is independently hydrogen, halogen, cyano, ═O,—OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³,—OC(O)R¹³, —SR¹³, —S(O)R¹³, —S(O)₂R¹³, —S(O)₂NR¹³R¹⁴, (C₁-C₁₀)alkyloptionally substituted with one or more R¹², (C₁-C₁₀)heteroalkyloptionally substituted with one or more R¹², (C₃-C₁₀)cycloalkyloptionally substituted with one or more R¹², (C₇-C₁₂)aralkyl optionallysubstituted with one or more R¹², (C₃-C₂)heteroaralkyl optionallysubstituted with one or more R¹², (6 to 10 membered)aryl optionallysubstituted with one or more R¹², (5 to 10 membered)heteroaryloptionally substituted with one or more R¹², or (3 to 12membered)heterocyclyl optionally substituted with one or more R¹²;

each occurrence of R¹² is independently hydrogen, (C₁-C₆)alkyloptionally substituted with one or more R¹³, (C₃-C₆)cycloalkyloptionally substituted with one or more R¹³, halogen, cyano, ═O, —OR¹³,—NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³,—SR¹³, —S(O)R¹³, —S(O)₂R¹³, or —S(O)₂NR¹³R¹⁴;

each occurrence of R¹³ and R¹⁴ is independently hydrogen, (C₁-C₆)alkyl,(C₁-C₆) heteroalkyl, (C₃-C₆)cycloalkyl, (C₇-C₁₀)aralkyl;(C₃-C₁₂)heteroaralkyl, (6 to 10 membered)aryl, (5 to 10membered)heteroaryl, or (3 to 12 membered)heterocyclyl; or R¹³ and R¹⁴together may form a 3 to 10 membered ring; and

u is 2 or 3; and

p and q are each independently 0, 1, or 2, provided that when one of pand q is 0, the other is 1 or 2.

In one embodiment, L is —C(R⁶)₂—C(R⁶)₂—, —C(R⁶)═C(R⁶)—, —N(R¹⁰)—C(R⁶)₂—,—O—C(R⁶)₂—, —C(R⁶)₂—N(R¹⁰)—, —C(R⁶)₂—O—, —C(R⁶)₂—S—, or —S—.

In one embodiment, L is —C(R⁶)₂—C(R⁶)₂—. In one embodiment, L is—C(R⁶)═C(R⁶)—. In one embodiment, L is —N(R¹⁰)—C(R⁶)₂—. In oneembodiment, L is —O—C(R⁶)₂—. In one embodiment, L is —C(R⁶)₂—N(R¹⁰)—. Inone embodiment, L is —C(R⁶)₂—O—.

In one embodiment, L is —C(R⁶)₂—S—. In one embodiment, L is —S—.

In one embodiment, L is —(CH₂)_(p)—S—(CH₂)_(q)—, —CH═CH—, or—(CH₂)_(u)—. In one embodiment, L is —(CH₂)_(p)—S—(CH₂)_(q)—. In oneembodiment, L is —CH═CH—. In one embodiment, L is —(CH₂)_(u)—.

In one embodiment, A is

In one embodiment, A is

In one embodiment, -A¹-A²- is —NR⁷—C(═O)—. In one embodiment, -A¹-A²- is—C(═O)—NR⁷—. In one embodiment, -A¹-A²- is —O—C(═O)—. In one embodiment,-A¹-A- is —C(═O)—O—. In one embodiment, -A¹-A²- is —N═CR⁸—. In oneembodiment, -A¹-A²- is —CR⁸═N—. In one embodiment, -A¹-A²- is —CR⁸═CR⁸—.In one embodiment, -A¹-A²- is —N═N—.

In one embodiment, A³ is N. In one embodiment, A³ is CR⁹.

In one embodiment, A⁴ is NR⁵. In one embodiment, A⁴ is O. In oneembodiment, A⁴ is S.

In one embodiment, A⁵ is N. In one embodiment, A⁵ is CR⁵.

In one embodiment, A⁶ is N. In one embodiment, A⁶ is CR⁵.

In one embodiment, R¹ is hydrogen. In one embodiment, R¹ is cyano. Inone embodiment, R¹ is halo. In one embodiment, R¹ is optionallysubstituted (C₁-C₁₀)alkyl. In one embodiment, R¹ is optionallysubstituted (C₂-C₁₀)alkenyl. In one embodiment, R¹ is optionallysubstituted (C₁-C₁₀)alkoxyl. In one embodiment, R¹ is optionallysubstituted (C₁-C₁₀)aminoalkyl. In one embodiment, R¹ is optionallysubstituted (C₁-C₁₀)heteroalkyl. In one embodiment, R¹ is optionallysubstituted (C₃-C₁₀)cycloalkyl. In one embodiment, R¹ is optionallysubstituted (6 to 10 membered)aryl. In one embodiment, R¹ is optionallysubstituted (5 to 10 membered)heteroaryl. In one embodiment, R¹ isoptionally substituted (3 to 12 membered)heterocyclyl. In oneembodiment, R¹ is optionally substituted hydroxyl. In one embodiment, R¹is optionally substituted amino. In one embodiment, R¹ is optionallysubstituted imino. In one embodiment, R¹ is optionally substitutedamido. In one embodiment, R¹ is optionally substituted carbonyl. In oneembodiment, R¹ is optionally substituted thiol. In one embodiment, R¹ isoptionally substituted sulfinyl. In one embodiment, R¹ is optionallysubstituted sulfonyl. In one embodiment, R¹ is optionally substitutedwith one or more R¹

In one embodiment, R² is hydrogen. In one embodiment, R² is cyano. Inone embodiment, R² is halo. In one embodiment, R² is optionallysubstituted (C₁-C₁₀)alkyl. In one embodiment, R² is optionallysubstituted (C₂-C₁₀)alkenyl. In one embodiment, R² is optionallysubstituted (C₁-C₁₀)alkoxyl. In one embodiment, R² is optionallysubstituted (C₁-C₁₀)aminoalkyl. In one embodiment, R² is optionallysubstituted (C₁-C₁₀)heteroalkyl. In one embodiment, R² is optionallysubstituted (C₃-C₁₀)cycloalkyl. In one embodiment, R² is optionallysubstituted (6 to 10 membered)aryl. In one embodiment, R² is optionallysubstituted (5 to 10 membered)heteroaryl. In one embodiment, R² isoptionally substituted (3 to 12 membered)heterocyclyl. In oneembodiment, R² is optionally substituted hydroxyl. In one embodiment, R²is optionally substituted amino. In one embodiment, R² is optionallysubstituted imino. In one embodiment, R² is optionally substitutedamido. In one embodiment, R² is optionally substituted carbonyl. In oneembodiment, R² is optionally substituted thiol. In one embodiment, R² isoptionally substituted sulfinyl. In one embodiment, R² is optionallysubstituted sulfonyl. In one embodiment, R² is optionally substitutedwith one or more R¹.

In one embodiment, R¹ and R² together with the atoms to which they areattached form a ring optionally substituted with one or more R¹¹. In oneembodiment, R¹ and R² together with the atoms to which they are attachedform an optionally substituted aromatic ring. In one embodiment, R¹ andR² together with the atoms to which they are attached form an optionallysubstituted non-aromatic ring. In one embodiment, R¹ and R² togetherwith the atoms to which they are attached form an optionally substitutedpartially saturated ring. In one embodiment, R¹ and R² together with theatoms to which they are attached form an optionally substituted5-membered ring (which is further fused to the adjacent 6-membered ringto form a 9-membered fused ring system). In one embodiment, R¹ and R²together with the atoms to which they are attached form an optionallysubstituted 6-membered ring (which is further fused to the adjacent6-membered ring to form a 10-membered fused ring system). In oneembodiment, R¹ and R² together with the atoms to which they are attachedform an optionally substituted 9-membered ring (which is further fusedto the adjacent 6-membered ring to form a 13-membered fused ringsystem). In one embodiment, R¹ and R² together with the atoms to whichthey are attached form an optionally substituted 10-membered ring (whichis further fused to the adjacent 6-membered ring to form a 14-memberedfused ring system). In one embodiment, R¹ and R² together with the atomsto which they are attached form an optionally substituted phenyl ring.In one embodiment, R¹ and R² together with the atoms to which they areattached form an optionally substituted pyridyl ring. In one embodiment,R¹ and R² together with the atoms to which they are attached form anoptionally substituted pyrimidinyl ring. In one embodiment, R¹ and R²together with the atoms to which they are attached form an optionallysubstituted pyrazinyl ring. In one embodiment, R¹ and R² together withthe atoms to which they are attached form an optionally substitutedbcnzothiophenyl ring. In one embodiment, R¹ and R² together with theatoms to which they are attached form an optionally substitutedbenzofuranyl ring. In one embodiment, R¹ and R² together with the atomsto which they are attached form an optionally substituted indolyl ring.In one embodiment, R¹ and R² together with the atoms to which they areattached form an optionally substituted benzimidazolyl ring. In oneembodiment, R¹ and R² together with the atoms to which they are attachedform an optionally substituted benzoxazolyl ring. In one embodiment, R¹and R² together with the atoms to which they are attached form anoptionally substituted benzothiazolyl ring. In one embodiment, R¹ and R²together with the atoms to which they are attached form an optionallysubstituted thienopyridinyl ring. In one embodiment, R¹ and R² togetherwith the atoms to which they are attached form an optionally substitutedfuropyridinyl ring. In one embodiment, R and R² together with the atomsto which they are attached form an optionally substitutedpyrrolopyridinyl ring. In one embodiment, R¹ and R² together with theatoms to which they are attached form an optionally substituted naphthylring. In one embodiment, R and R² together with the atoms to which theyare attached form an optionally substituted quinoxalinyl ring. In oneembodiment, R¹ and R² together with the atoms to which they are attachedform an optionally substituted quinazolinyl ring. In one embodiment, R¹and R² together with the atoms to which they are attached form anoptionally substituted cinnolinyl ring. In one embodiment, R¹ and R²together with the atoms to which they are attached form an optionallysubstituted naphthyridinyl ring. In one embodiment, R¹ and R² togetherwith the atoms to which they are attached form an optionally substitutedquinolinyl ring. In one embodiment, R¹ and R² together with the atoms towhich they are attached form an optionally substitutedbenzo[d][1,3]dioxolyl ring. In one embodiment, R¹ and R² together withthe atoms to which they are attached form an optionally substituted5-membered heteroaryl ring (e.g., pyrrole, pyrazole, imidazole,triazole, oxazole, thiazole, isoxazole, isothiazole, furan, andthiophene). In one embodiment, R¹ and R² together with the atoms towhich they are attached form an optionally substituted ring having oneor more (in one embodiment, one, two, three, or four) additionalhetero-atoms selected from the group consisting of O, S, and N. In oneembodiment, R¹ and R² together with the atoms to which they are attachedform an optionally substituted ring having no additional hetero-atom.

In one embodiment, R³ is hydrogen. In one embodiment, R³ is cyano. Inone embodiment, R³ is halo. In one embodiment, R³ is optionallysubstituted (C₁-C₁₀)alkyl. In one embodiment, R³ is optionallysubstituted (C₂-C₁₀)alkenyl. In one embodiment, R³ is optionallysubstituted (C₁-C₁₀)alkoxyl. In one embodiment, R³ is optionallysubstituted (C₁-C₁₀)aminoalkyl. In one embodiment, R³ is optionallysubstituted (C₁-C₁₀)heteroalkyl. In one embodiment, R³ is optionallysubstituted (C₃-C₁₀)cycloalkyl. In one embodiment, R³ is optionallysubstituted (6 to 10 membered)aryl. In one embodiment, R³ is optionallysubstituted (5 to 10 membered)heteroaryl. In one embodiment, R³ isoptionally substituted (3 to 12 membered)heterocyclyl. In oneembodiment, R³ is optionally substituted hydroxyl. In one embodiment, R³is optionally substituted amino. In one embodiment, R³ is optionallysubstituted imino. In one embodiment, R³ is optionally substitutedamido. In one embodiment, R³ is optionally substituted carbonyl. In oneembodiment, R³ is optionally substituted thiol. In one embodiment, R³ isoptionally substituted sulfinyl. In one embodiment, R³ is optionallysubstituted sulfonyl. In one embodiment, R³ is optionally substitutedwith one or more R¹¹. In one embodiment, R³ is (i) hydrogen; or (ii)(C₁—Co)alkyl, (C₂-C₁₀)alkenyl, (C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl,(6 to 10 membered)aryl, (5 to 10 membered) heteroaryl, (3 to 12membered)heterocyclyl, carbonyl, or sulfonyl, each of which isoptionally substituted with one or more R¹¹.

In one embodiment, R⁴ is hydrogen. In one embodiment, R⁴ is cyano. Inone embodiment, R⁴ is halo. In one embodiment, R⁴ is optionallysubstituted (C₁-C₁₀)alkyl. In one embodiment, R⁴ is optionallysubstituted (C₂-C₁₀)alkenyl. In one embodiment, R⁴ is optionallysubstituted (C₁-C₁₀)alkoxyl. In one embodiment, R⁴ is optionallysubstituted (C₁-C₁₀)aminoalkyl. In one embodiment, R⁴ is optionallysubstituted (C₁-C₁₀)heteroalkyl. In one embodiment, R⁴ is optionallysubstituted (C₃-C₁₀)cycloalkyl. In one embodiment, R⁴ is optionallysubstituted (6 to 10 membered)aryl. In one embodiment, R⁴ is optionallysubstituted (5 to 10 membered)heteroaryl. In one embodiment, R⁴ isoptionally substituted (3 to 12 membered)heterocyclyl. In oneembodiment, R⁴ is optionally substituted hydroxyl. In one embodiment, R⁴is optionally substituted amino. In one embodiment, R⁴ is optionallysubstituted imino. In one embodiment, R⁴ is optionally substitutedamido. In one embodiment, R⁴ is optionally substituted carbonyl. In oneembodiment, R⁴ is optionally substituted thiol. In one embodiment, R⁴ isoptionally substituted sulfinyl. In one embodiment, R⁴ is optionallysubstituted sulfonyl. In one embodiment, R⁴ is optionally substitutedwith one or more R¹¹.

In one embodiment, R⁴ is (i) hydrogen; or (ii) (C₁-C₁₀)alkyl,(C₂-C₁₀)alkenyl, (C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10membered)aryl, (5 to 10 membered) heteroaryl, (3 to 12membered)heterocyclyl, carbonyl, or sulfonyl, each of which isoptionally substituted with one or more R¹¹.

In one embodiment, R³ and R⁴ together with the atoms to which they areattached form a ring optionally substituted with one or more R¹¹. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform an optionally substituted 5-membered ring (which is further fusedto the adjacent 5- or 6-membered ring). In one embodiment, R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted 6-membered ring (which is further fused to the adjacent 5-or 6-membered ring). In one embodiment, R³ and R⁴ together with theatoms to which they are attached form an optionally substituted9-membered ring (which is further fused to the adjacent 5- or 6-memberedring). In one embodiment, R³ and R⁴ together with the atoms to whichthey are attached form an optionally substituted 10-membered ring (whichis further fused to the adjacent 5- or 6-membered ring). In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform an optionally substituted aromatic ring. In one embodiment, R³ andR⁴ together with the atoms to which they are attached form an optionallysubstituted non-aromatic ring. In one embodiment, R³ and R⁴ togetherwith the atoms to which they are attached form an optionally substitutedpartially saturated ring. In one embodiment, R³ and R⁴ together with theatoms to which they are attached form an optionally substituted phenylring. In one embodiment, R³ and R⁴ together with the atoms to which theyare attached form an optionally substituted pyridyl ring. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform an optionally substituted pyrimidinyl ring. In one embodiment, R³and R⁴ together with the atoms to which they are attached form anoptionally substituted pyrazinyl ring. In one embodiment, R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted benzothiophenyl ring. In one embodiment, R³ and R⁴ togetherwith the atoms to which they are attached form an optionally substitutedbenzofuranyl ring. In one embodiment, R¹ and R⁴ together with the atomsto which they are attached form an optionally substituted indolyl ring.In one embodiment, R³ and R⁴ together with the atoms to which they areattached form an optionally substituted benzimidazolyl ring. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform an optionally substituted benzoxazolyl ring. In one embodiment, R³and R⁴ together with the atoms to which they are attached form anoptionally substituted benzothiazolyl ring. In one embodiment, R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted thienopyridinyl ring. In one embodiment, R³ and R⁴ togetherwith the atoms to which they are attached form an optionally substitutedfuropyridinyl ring. In one embodiment, R³ and R⁴ together with the atomsto which they are attached form an optionally substitutedpyrrolopyridinyl ring. In one embodiment, R³ and R⁴ together with theatoms to which they are attached form an optionally substituted naphthylring. In one embodiment, R³ and R⁴ together with the atoms to which theyare attached form an optionally substituted quinoxalinyl ring. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform an optionally substituted quinazolinyl ring. In one embodiment, R³and R⁴ together with the atoms to which they are attached form anoptionally substituted cinnolinyl ring. In one embodiment, R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted naphthyridinyl ring. In one embodiment, R³ and R⁴ togetherwith the atoms to which they are attached form an optionally substitutedquinolinyl ring. In one embodiment, R³ and R⁴ together with the atoms towhich they are attached form an optionally substitutedbenzo[d][1,3]dioxolyl ring. In one embodiment, R³ and R⁴ together withthe atoms to which they are attached form an optionally substituted5-membered non-aromatic ring. In one embodiment, R³ and R⁴ together withthe atoms to which they are attached form an optionally substituted6-membered non-aromatic ring. In one embodiment, R³ and R⁴ together withthe atoms to which they are attached form an optionally substituted9-membered non-aromatic ring. In one embodiment, R³ and R⁴ together withthe atoms to which they are attached form an optionally substituted10-membered non-aromatic ring. In one embodiment, R³ and R⁴ togetherwith the atoms to which they are attached form an optionally substituted9-membered partially saturated ring. In one embodiment, R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted 10-membered partially saturated ring. In one embodiment, R³and R⁴ together with the atoms to which they are attached form anoptionally substituted ring having one or more (in one embodiment, one,two, three, or four) additional heteroatoms selected from the groupconsisting of O, S, and N. In one embodiment, R³ and R⁴ together withthe atoms to which they are attached form an optionally substituted ringhaving no additional heteroatom.

In one embodiment, R⁵ is hydrogen. In one embodiment, R⁵ is cyano. Inone embodiment, R⁵ is halo. In one embodiment, R⁵ is optionallysubstituted (C₁-C₁₀)alkyl. In one embodiment, R⁵ is optionallysubstituted (C₂-C₁₀)alkenyl. In one embodiment, R⁵ is optionallysubstituted (C₁-C₁₀)alkoxyl. In one embodiment, R⁵ is optionallysubstituted (C₁-C₁₀)aminoalkyl. In one embodiment, R⁵ is optionallysubstituted (C₁-C₁₀)heteroalkyl. In one embodiment, R⁵ is optionallysubstituted (C₃-C₁₀)cycloalkyl. In one embodiment, R⁵ is optionallysubstituted (6 to 10 membered)aryl. In one embodiment, R⁵ is optionallysubstituted (5 to 10 membered)heteroaryl. In one embodiment, R⁵ isoptionally substituted (3 to 12 membered)heterocyclyl. In oneembodiment, R⁵ is optionally substituted hydroxyl. In one embodiment, R⁵is optionally substituted amino. In one embodiment, R⁵ is optionallysubstituted imino. In one embodiment, R⁵ is optionally substitutedamido. In one embodiment, R⁵ is optionally substituted carbonyl. In oneembodiment, R⁵ is optionally substituted thiol. In one embodiment, R⁵ isoptionally substituted sulfinyl. In one embodiment, R⁵ is optionallysubstituted sulfonyl. In one embodiment, R⁵ is optionally substitutedwith one or more R¹¹.

In one embodiment, R⁵ is (i) hydrogen; or (ii) (C₁-C₁₀)alkyl,(C₂-C₁₀)alkenyl, (C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10membered)aryl, (5 to 10 membered) heteroaryl, (3 to 12membered)heterocyclyl, carbonyl, or sulfonyl, each of which isoptionally substituted with one or more R¹¹.

In one embodiment, R⁴ and R⁵ together with the atoms to which they areattached form a ring optionally substituted with one or more R¹¹. In oneembodiment, R⁴ and R⁵ together with the atoms to which they are attachedform an optionally substituted 5-membered ring (which is further fusedto the adjacent 5- or 6-membered ring). In one embodiment, R⁴ and R⁵together with the atoms to which they are attached form an optionallysubstituted 6-membered ring (which is further fused to the adjacent 5-or 6-membered ring). In one embodiment, R⁴ and R⁵ together with theatoms to which they are attached form an optionally substituted9-membered ring (which is further fused to the adjacent 5- or 6-memberedring). In one embodiment, R⁴ and R⁵ together with the atoms to whichthey are attached form an optionally substituted 10-membered ring (whichis further fused to the adjacent 5- or 6-membered ring). In oneembodiment, R⁴ and R⁵ together with the atoms to which they are attachedform an optionally substituted aromatic ring. In one embodiment, R⁴ andR⁵ together with the atoms to which they are attached form an optionallysubstituted non-aromatic ring. In one embodiment, R⁴ and R⁵ togetherwith the atoms to which they are attached form an optionally substitutedpartially saturated ring. In one embodiment, R⁴ and R⁵ together with theatoms to which they are attached form an optionally substituted ringhaving one or more (in one embodiment, one, two, three, or four)additional hetero-atoms selected from the group consisting of O, S, andN. In one embodiment, R⁴ and R⁵ together with the atoms to which theyare attached form an optionally substituted ring having no additionalhetero-atom.

In one embodiment, R¹⁹ is hydrogen. In one embodiment, R¹⁹ is cyano. Inone embodiment, R¹⁹ is halo. In one embodiment, R¹⁹ is optionallysubstituted (C₁-C₁₀)alkyl. In one embodiment, R¹⁹ is optionallysubstituted (C₂-C₁₀)alkenyl. In one embodiment, R¹⁹ is optionallysubstituted (C₁-C₁₀)alkoxyl. In one embodiment, R¹⁹ is optionallysubstituted (C₁-C₁₀)aminoalkyl. In one embodiment, R¹⁹ is optionallysubstituted (C₁-C₁₀)heteroalkyl. In one embodiment, R¹⁹ is optionallysubstituted (C₃-C₁₀)cycloalkyl. In one embodiment, R¹⁹ is optionallysubstituted (6 to 10 membered) aryl. In one embodiment, R¹⁹ isoptionally substituted (5 to 10 membered)heteroaryl. In one embodiment,R¹⁹ is optionally substituted (3 to 12 membered)heterocyclyl. In oneembodiment, R¹⁹ is optionally substituted hydroxyl. In one embodiment,R¹⁹ is optionally substituted amino. In one embodiment, R¹⁹ isoptionally substituted imino. In one embodiment, R¹⁹ is optionallysubstituted amido. In one embodiment, R¹⁹ is optionally substitutedcarbonyl. In one embodiment, R¹⁹ is optionally substituted thiol. In oneembodiment, R¹⁹ is optionally substituted sulfinyl. In one embodiment,R¹⁹ is optionally substituted sulfonyl. In one embodiment, R⁹ isoptionally substituted with one or more R¹¹.

In one embodiment, R²⁰ is hydrogen. In one embodiment, R²⁰ is optionallysubstituted (C₁-C₁₀)alkyl. In one embodiment, R²⁰ is optionallysubstituted (C₂-C₁₀)alkenyl. In one embodiment, R²⁰ is optionallysubstituted (C₁-C₁₀)heteroalkyl. In one embodiment, R²⁰ is optionallysubstituted (C₃-C₁₀)cycloalkyl. In one embodiment, R²⁰ is optionallysubstituted (6 to 10 membered)aryl. In one embodiment, R²⁰ is optionallysubstituted (5 to 10 membered)heteroaryl. In one embodiment, R⁸ isoptionally substituted (3 to 12 membered)heterocyclyl. In oneembodiment, R²⁰ is optionally substituted carbonyl. In one embodiment,R²⁰ is optionally substituted sulfonyl. In one embodiment, R²⁰ isoptionally substituted with one or more R¹¹.

In one embodiment, R⁶ is hydrogen. In one embodiment, R⁶ is halo. In oneembodiment, R⁶ is (C₁-C₆)alkyl optionally substituted with one or morehalo.

In one embodiment, R⁷ is hydrogen. In one embodiment, R⁷ is (C₁-C₆)alkyloptionally substituted with one or more halo.

In one embodiment, R⁸ is hydrogen. In one embodiment, R⁸ is cyano. Inone embodiment, R⁸ is halo. In one embodiment, R⁸ is optionallysubstituted (C₁-C₁₀)alkyl. In one embodiment, R⁸ is optionallysubstituted (C₂-C₁₀)alkenyl. In one embodiment, R⁸ is optionallysubstituted (C₁-C₁₀)alkoxyl. In one embodiment, R⁸ is optionallysubstituted (C₁-C₁₀)aminoalkyl. In one embodiment, R⁸ is optionallysubstituted (C₁-C₁₀)heteroalkyl. In one embodiment, R⁸ is optionallysubstituted (C₃-C₁₀)cycloalkyl. In one embodiment, R⁸ is optionallysubstituted (6 to 10 membered)aryl. In one embodiment, R⁸ is optionallysubstituted (5 to 10 membered)heteroaryl. In one embodiment, R⁸ isoptionally substituted (3 to 12 membered)heterocyclyl. In oneembodiment, R⁸ is optionally substituted hydroxyl. In one embodiment, R⁸is optionally substituted amino. In one embodiment, R⁸ is optionallysubstituted imino. In one embodiment, R⁸ is optionally substitutedamido. In one embodiment, R⁸ is optionally substituted carbonyl. In oneembodiment, R⁸ is optionally substituted thiol. In one embodiment, R⁸ isoptionally substituted sulfinyl. In one embodiment, R⁸ is optionallysubstituted sulfonyl. In one embodiment, R⁸ is optionally substitutedwith one or more R¹¹.

In one embodiment, R⁹ is hydrogen. In one embodiment, R⁹ is cyano. Inone embodiment, R⁹ is halo. In one embodiment, R⁹ is (C₁-C₆)alkyloptionally substituted with one or more halo. In one embodiment, R⁹ is(C₁-C₆)alkoxyl optionally substituted with one or more halo.

In one embodiment, R¹⁰ is hydrogen. In one embodiment, R¹⁰ is(C₁-C₆)alkyl optionally substituted with one or more halo.

In one embodiment, R¹¹ is hydrogen. In one embodiment, R¹¹ is halogen.In one embodiment, R¹ is cyano. In one embodiment, R¹¹ is ═O. In oneembodiment, R¹ is —OR¹³. In one embodiment, R¹ is —NR¹³R¹⁴. In oneembodiment, R¹¹ is —N(R¹³)C(O)R¹⁴. In one embodiment, R¹¹ is—C(O)NR¹³R¹⁴. In one embodiment, R¹¹ is —C(O)R¹³. In one embodiment, R¹¹is —C(O)OR¹³. In one embodiment, R¹¹ is —OC(O)R¹³. In one embodiment,R¹¹ is —SR¹³. In one embodiment, R¹¹ is —S(O)R¹³. In one embodiment, R¹¹is —S(O)₂R³. In one embodiment, R¹¹ is —S(O)₂NR¹³R¹⁴. In one embodiment,R¹¹ is (C₁-C₁₀)alkyl optionally substituted with one or more R¹². In oneembodiment, R¹¹ is (C₁-C₁₀)heteroalkyl optionally substituted with oneor more R¹². In one embodiment, R¹¹ is (C₃-C₁₀)cycloalkyl optionallysubstituted with one or more R¹². In one embodiment, R¹¹ is(C₃-C₁₂)aralkyl optionally substituted with one or more R¹². In oneembodiment, R¹¹ is (C₃-C₁₂)heteroaralkyl optionally substituted with oneor more R¹². In one embodiment, R¹¹ is (6 to 10 membered)aryl optionallysubstituted with one or more R¹². In one embodiment, R¹¹ is (5 to 10membered)heteroaryl optionally substituted with one or more R¹². In oneembodiment, R¹¹ is (3 to 12 membered)heterocyclyl optionally substitutedwith one or more R¹².

In one embodiment, R¹² is hydrogen. In one embodiment, R¹² is(C₁-C₆)alkyl optionally substituted with one or more R¹³. In oneembodiment, R¹² is (C₃-C₆)cycloalkyl optionally substituted with one ormore R¹³. In one embodiment, R¹² is halogen. In one embodiment, R¹² iscyano. In one embodiment, R¹² is ═O. In one embodiment, R¹² is —OR¹³. Inone embodiment, R¹² is —NR¹³R¹⁴. In one embodiment, R¹² is—N(R¹³)C(O)R¹⁴. In one embodiment, R¹² is —C(O)NR¹³R¹⁴. In oneembodiment, R¹² is —C(O)R¹³. In one embodiment, R¹² is —C(O)OR¹³. In oneembodiment, R¹² is —OC(O)R¹³. In one embodiment, R¹² is —SR¹³. In oneembodiment, R¹² is —S(O)R¹³. In one embodiment, R¹² is —S(O)₂R¹³. In oneembodiment, R¹² is —S(O)₂NR¹³R¹⁴.

In one embodiment, R¹³ is hydrogen. In one embodiment, R¹³ is(C₁-C₆)alkyl. In one embodiment, R¹³ is (C₁-C₆)heteroalkyl. In oneembodiment, R¹³ is (C₃-C₆)cycloalkyl. In one embodiment, R¹³ is(C₇-C₁₀)aralkyl. In one embodiment, R¹³ is (C₃-C₁₂)heteroaralkyl. In oneembodiment, R¹³ is (6 to 10 membered)aryl. In one embodiment, R¹³ is (5to 10 membered)heteroaryl. In one embodiment, R¹³ is (3 to 12membered)heterocyclyl.

In one embodiment, R¹⁴ is hydrogen. In one embodiment, R¹⁴ is(C₁-C₆)alkyl. In one embodiment, R¹⁴ is (C₁-C₆)heteroalkyl. In oneembodiment, R¹⁴ is (C₃-C₆)cycloalkyl. In one embodiment, R¹⁴ is(C₇-C₁₀)aralkyl. In one embodiment, R¹⁴ is (C₃-C₁₂)heteroaralkyl. In oneembodiment, R¹⁴ is (6 to 10 membered)aryl. In one embodiment, R¹⁴ is (5to 10 membered)heteroaryl. In one embodiment, R¹⁴ is (3 to 12membered)heterocyclyl.

In one embodiment, R¹³ and R¹⁴ together form a 3 to 10 membered ring.

In one embodiment, u is 2. In one embodiment, u is 3.

In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment,p is 2.

In one embodiment, q is 0. In one embodiment, q is 1. In one embodiment,q is 2. In one embodiment, p is 0 and q is 1 or 2. In one embodiment, qis 0 and p is 1 or 2.

Any of the combinations of A, B, L, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R⁴, R¹⁹, R²⁰, A¹, A², A³, A⁴, A⁵, A⁶, u, p, and qare encompassed by this disclosure and specifically provided herein.

In one embodiment, L is —CH₂—CH₂—, —CH═CH—, —O—CH₂—, —NH—CH₂—, —CH₂—O—,—CH₂—NH—, —CH₂—S—, or —S—. In one embodiment, L is —CH₂—CH₂—. In oneembodiment, L is —CH═CH—. In one embodiment, L is —O—CH₂. In oneembodiment, L is —NH—CH₂—. In one embodiment, L is —CH₂—O—. In oneembodiment, L is —CH₂—NH—. In one embodiment, L is —CH₂—S—. In oneembodiment, L is —S—.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

A is

wherein R¹, R², A¹, and A² are defined herein elsewhere.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein R³, R⁴ and A⁴ are defined herein elsewhere.

In one embodiment, provided herein is a compound of formula (I-A), or apharmaceutically acceptable salt or stereoisomer thereof,

wherein R¹, R², R³, R⁴, A¹, A², A⁴ and L are defined herein elsewhere.

In one embodiment, L is —(CH₂)₂— or —CH═CH—. In one embodiment, A¹-A² isCR⁸═CR⁸ such that A is pyridine, CR⁸═N such that A is pyrimidine, orN═CR⁸ such that A is pyrazine, optionally substituted with one or moresubstituent(s) selected from R¹, R², and R⁸, wherein R¹, R², and R⁸ aredefined herein elsewhere. In one embodiment, A is pyridine, pyrimidine,or pyrazine, optionally substituted with one or more methyl, ethyl, CF₃,halo (e.g., F, Cl, or Br), cyano, carboxamido, imidazolyl, or pyridyl;or two adjacent substituents together with the atoms to which they areattached form a 5- or 6-membered ring. In one embodiment, A isoptionally substituted quinoxalin-2(1H)-one. In one embodiment, R³ isoptionally substituted phenyl or pyridyl. In one embodiment, A⁴ is NR⁵,and R⁵ is (i) hydrogen; or (ii) (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl,(C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10 membered) aryl, (5 to10 membered) heteroaryl, (3 to 12 membered) heterocyclyl, carbonyl, orsulfonyl, each of which is optionally substituted with one or more R¹¹;or (iii) R⁴ and R⁵ together with the atoms to which they are attachedform a ring optionally substituted with one or more R¹¹. In oneembodiment, R⁵ is hydrogen or methyl. In one embodiment, R⁴ is H. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform an optionally substituted aryl or heteroaryl (e.g., benzene,pyridine, naphthylene, or quinoline). In one embodiment, A is optionallysubstituted pyridyl. In one embodiment, A is optionally substitutedpyrimidyl. In one embodiment, A is optionally substituted pyridazinyl.In one embodiment, A is optionally substituted with one or more halo,cyano, hydroxyl, methyl, ethyl, CF₃, methoxy, ethoxy, OCF₃, amido, aryl,heteroaryl, cycloalkyl, or heterocyclyl. Specific examples include, butare not limited to, the following:

In one embodiment, A⁶ is CH or N.

In one embodiment, R³ is hydrogen. In one embodiment, R³ is halo (e.g.,F, Cl, or Br) or cyano. In one embodiment, R³ is methyl, phenyl,pyridyl, furanyl, thienyl, benzofuranyl, naphthyl, quinolinyl, orbenzodioxolyl, each of which is optionally substituted with one or moreR¹¹. In one embodiment, R³ is methyl, phenyl or pyridyl, each of whichis optionally substituted with one or more R¹¹. In one embodiment, R³ isalkyl, aryl, or heteroaryl, each of which is optionally substituted withone or more R¹¹.

In one embodiment, R⁴ is hydrogen. In one embodiment, R⁴ is halo (e.g.,F, Cl, or Br) or cyano. In one embodiment, R⁴ is methyl, phenyl orpyridyl, each of which is optionally substituted with one or more R¹¹.In one embodiment, R⁴ is methyl, phenyl, pyridyl, furanyl, thienyl,benzofuranyl, naphthyl, quinolinyl, or benzodioxolyl, each of which isoptionally substituted with one or more R¹¹. In one embodiment, R⁴ isalkyl, aryl, or heteroaryl, each of which is optionally substituted withone or more R¹¹.

In one embodiment, R³ and R⁴ together with the atoms to which they areattached form a phenyl, pyridyl, pyrimidyl, pyrazinyl, naphthyl,quinolinyl, or benzodioxolyl ring, which is optionally substituted withone or more R¹¹.

In one embodiment, each occurrence of R⁸ is independently hydrogen, halo(e.g., F, Cl, or Br), cyano, CH₃, OCH₃, CF₃, or OCF₃. In one embodiment,each occurrence of R⁸ is independently hydrogen, fluoro, chloro, cyano,CH₃, or CF₃. In one embodiment, each occurrence of R⁸ is independentlyhydrogen or CH₃. In one embodiment, R⁸ is hydrogen.

In one embodiment, each occurrence of R¹¹ is independently hydrogen,fluoro, chloro, CH₃, OCH₃, CF₃, OCF₃, OH, ethyl, propyl, isopropyl,t-butyl, or phenyl.

In one embodiment, B is selected from the group consisting of:

wherein R³, R⁴, R⁵, R¹¹, and A⁴ are defined herein elsewhere; k is 0, 1,2, 3, or 4; each occurrence of G is independently CH or N; and J is O,S, NH or CH₂.

In one embodiment, R³ is hydrogen. In one embodiment, R³ is alkyl, aryl,or heteroaryl, each of which is optionally substituted with one or moreR¹¹. In one embodiment, R³ is (i) hydrogen; or (ii) alkyl, aryl, orheteroaryl, each of which is optionally substituted with one or moreR¹¹.

In one embodiment, R⁴ is hydrogen. In one embodiment, R⁴ is alkyl, aryl,or heteroaryl, each of which is optionally substituted with one or moreR¹¹. In one embodiment, R⁴ is (i) hydrogen; or (ii) alkyl, aryl, orheteroaryl, each of which is optionally substituted with one or more R¹¹

In one embodiment, R⁵ is hydrogen. In one embodiment, R⁵ is alkyl, aryl,or heteroaryl, each of which is optionally substituted with one or moreR¹¹. In one embodiment, R⁵ is (i) hydrogen; or (ii) alkyl, aryl, orheteroaryl, each of which is optionally substituted with one or moreR¹¹.

In one embodiment, R¹¹ is hydrogen. In one embodiment, R¹¹ is alky, arylor heteroaryl, each of which is optionally substituted with one or moreR¹². In one embodiment, A⁴ is O, S, NH, or NR⁵. In one embodiment, eachoccurrence of R¹¹ is independently (i) hydrogen; or (ii) alky, aryl orheteroaryl, each of which is optionally substituted with one or moreR¹².

In one embodiment, B is

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein L is —CH₂—CH₂—.

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein A⁴ is NR⁵.

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein A⁴ is NR⁵, and L is —CH₂—CH₂—.

In one embodiment, -A¹-A²- is —NR⁷—C(O)—. In one embodiment, -A¹-A² is—C(O)—NR⁷—. In one embodiment, -A¹-A²- is —N═CH—. In one embodiment,-A¹-A²- is —CH═N—. In one embodiment, -A¹-A²- is —CH═CH—. In oneembodiment, -A¹-A²- is —N═N—. In one embodiment, R⁷ is hydrogen. In oneembodiment, R⁷ is methyl. In one embodiment, R⁷ is alkyl. In oneembodiment, R¹ and R² together with the atoms to which they are attachedform a phenyl ring, optionally substituted with one or more R¹¹. In oneembodiment, R¹ and R² together with the atoms to which they are attachedform a pyridyl ring, optionally substituted with one or more R¹.

In one embodiment, provided herein is a compound of formula (I) or(I-A), or a pharmaceutically acceptable salt or stereoisomer thereof,wherein R¹ and R² together with the carbon atoms to which they areattached form an optionally substituted pyridyl ring. In one embodiment,A is optionally substituted pyrido[4,3-d]pyrimidin-4(3H)-one orpyrido[3,4-d]pyrimidin-4(3H)-one. In one embodiment, A ispyrido[2,3-b]pyrazine, pyrido[3,4-b]pyrazine, or naphthyridinyl, each ofwhich is optionally substituted. In one embodiment, A ispyridylpyrimidyl or naphthyridinyl, each of which is optionallysubstituted. In one embodiment, A is optionally substituted with one ormore halo (e.g., F, Cl, or Br), cyano, methyl, or CF₃. In oneembodiment, L is —(CH₂)₂— or —CH═CH—. In one embodiment, R³ isoptionally substituted phenyl or pyridyl (e.g., optionally substitutedwith one or more F, Cl, Br, cyano, methyl, or CF₃). In one embodiment,R⁴ is H. In one embodiment, A⁴ is NR⁵, and R⁵ is hydrogen or methyl. Inone embodiment, R³ and R⁴ together with the atoms to which they areattached form an optionally substituted aryl or heteroaryl (e.g.,benzene, pyridine, naphthylene, or quinoline). Specific examplesinclude, but are not limited to, the following:

In one embodiment, provided herein is a compound of formula (I) or(I-A), or a pharmaceutically acceptable salt or stereoisomer thereof,wherein

wherein R⁸ is defined herein elsewhere; each occurrence of R¹⁵ isindependently: (i) hydrogen, halo, cyano, —OR¹³, —NR¹³R¹⁴,—N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —SR¹³,—S(O)R¹³, —S(O)₂R¹³, —S(O)₂NR¹³R¹⁴, (C₁-C₁₀)alkyl optionally substitutedwith one or more R¹², (C₁-C₁₀)heteroalkyl optionally substituted withone or more R¹², (C₃-C₁)cycloalkyl optionally substituted with one ormore R², (C₇-C₁₂)aralkyl optionally substituted with one or more R¹²,(C₃-C₁₂)heteroaralkyl optionally substituted with one or more R¹², (6 to10 membered)aryl optionally substituted with one or more R¹², (5 to 10membered) heteroaryl optionally substituted with one or more R¹², or (3to 12 membered) heterocyclyl optionally substituted with one or moreR¹²; or (ii) when two occurrences of R¹⁵ are attached to adjacent carbonatoms, the two adjacent occurrences of R¹⁵ together with the carbonatoms to which they are attached may form a ring, optionally substitutedwith one or more R¹¹; wherein R¹¹, R¹², R¹³, and R¹⁴ are defined hereinelsewhere; and m is 0, 1, 2, 3, or 4. In one embodiment, R⁸ is hydrogenor methyl. In one embodiment, L is —(CH₂)₂— or —CH═CH—. In oneembodiment, L is —O—CH₂—, —NH—CH₂—, —CH₂—O—, —CH₂—S—, or —S—. In oneembodiment, A is quinoxalinyl optionally substituted with one or morehalo (e.g., F, Cl, or Br), cyano, methyl, ethyl, CF₃, OCH₃, or OCF₃. Inone embodiment, R³ is optionally substituted cycloalkyl (e.g.,cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), phenyl, pyridyl,furanyl, or thienyl (e.g., optionally substituted with one or more F,Cl, Br, cyano, methyl, or CF₃). In one embodiment, R⁴ is H. In oneembodiment, A⁴ is NR⁵, and R⁵ is hydrogen or methyl. In one embodiment,R³ and R⁴ together with the atoms to which they are attached form anoptionally substituted aryl or heteroaryl (e.g., phenyl, pyridyl,naphthyl, quinolinyl, tetrahydroquinolinyl, dihydrobenzodioxinyl, orbenzodioxolyl ring, in one embodiment, each of which is optionallysubstituted with one or more F, Cl, Br, cyano, methyl, ethyl, propyl,butyl, OH, OCH₃, CF₃, or OCF₃). In one embodiment, R⁴ and R⁵ togetherwith the atoms to which they are attached form an optionally substituted5- or 6-membered ring. In one embodiment, A⁴ is O or S. Specificexamples include, but are not limited to, the following:

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein

wherein each occurrence of R¹⁵ is independently: (i) hydrogen, halo,cyano, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³,—C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³, —S(O)₂R¹³, —S(O)₂NR¹³R¹⁴,(C₁-C₁₀)alkyl optionally substituted with one or more R¹²,(C₁-C₁₀)heteroalkyl optionally substituted with one or more R¹²,(C₃-C₁₀)cycloalkyl optionally substituted with one or more R¹²,(C₇-C₁₂)aralkyl optionally substituted with one or more R¹²,(C₃-C₁₂)heteroaralkyl optionally substituted with one or more R¹², (6 to10 membered)aryl optionally substituted with one or more R¹², (5 to 10membered) heteroaryl optionally substituted with one or more R¹², or (3to 12 membered)heterocyclyl optionally substituted with one or more R¹²;or (ii) when two occurrences of R¹⁵ are attached to adjacent carbonatoms, the two adjacent occurrences of R¹⁵ together with the carbonatoms to which they are attached may form a ring, optionally substitutedwith one or more R¹¹; wherein R¹¹, R¹², R¹³, and R¹⁴ are defined hereinelsewhere; and m is 0, 1, 2, 3, or 4. In one embodiment, R⁸ is hydrogenor methyl. In one embodiment, L is —(CH₂)₂— or —CH═CH—. In oneembodiment, A is quinolinyl optionally substituted with one or more halo(e.g., F, Cl, or Br), cyano, methyl, ethyl, CF₃, OCH₃, or OCF₃. In oneembodiment, A is optionally substituted phenanthrolinyl. In oneembodiment, R³ is optionally substituted phenyl, pyridyl, furanyl, orthienyl (e.g., optionally substituted with one or more F, Cl, Br, cyano,methyl, or CF₃). In one embodiment, R⁴ is H. In one embodiment, A⁴ isNR⁵, and R⁵ is hydrogen or methyl. In one embodiment, R³ and R⁴ togetherwith the atoms to which they are attached form an optionally substitutedaryl or heteroaryl (e.g., benzene, pyridine, naphthylene, or quinoline,in one embodiment, each of which is optionally substituted with one ormore F, Cl, Br, cyano, methyl, ethyl, propyl, butyl, OH, OCH₃, CF₃, orOCF₃). Specific examples include, but are not limited to, the following:

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein

wherein each occurrence of R¹⁵ is independently: (i) hydrogen, halo,cyano, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³,—C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³, —S(O)₂R¹³, —S(O)₂NR¹³R¹⁴,(C₁-C₁₀)alkyl optionally substituted with one or more R¹²,(C₃-C₁₂)heteroalkyl optionally substituted with one or more R¹²,(C₃-C₁₀)cycloalkyl optionally substituted with one or more R¹²,(C₇-C₁₂)aralkyl optionally substituted with one or more R¹²,(C₃-C₁₂)heteroaralkyl optionally substituted with one or more R¹², (6 to10 membered)aryl optionally substituted with one or more R¹², (5 to 10membered) heteroaryl optionally substituted with one or more R¹², or (3to 12 membered)heterocyclyl optionally substituted with one or more R¹²;or (ii) when two occurrences of R¹⁵ are attached to adjacent carbonatoms, the two adjacent occurrences of R¹⁵ together with the carbonatoms to which they are attached may form a ring, optionally substitutedwith one or more R¹¹; wherein R¹¹, R¹², R³, and R¹⁴ are defined hereinelsewhere; and m is 0, 1, 2, 3, or 4. In one embodiment, R⁸ is hydrogenor methyl. In one embodiment, L is —(CH₂)₂— or —CH═CH—. In oneembodiment, A is quinazolinyl optionally substituted with one or morehalo (e.g., F, CI, or Br), cyano, methyl, ethyl, CF₃, OCH₃, or OCF₃. Inone embodiment, R³ is optionally substituted phenyl, pyridyl, furanyl,or thienyl (e.g., optionally substituted with one or more F, Cl, Br,cyano, methyl, or CF₃). In one embodiment, R⁴ is H. In one embodiment,A⁴ is NR⁵, and R⁵ is hydrogen or methyl. In one embodiment, R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted aryl or heteroaryl (e.g., benzene, pyridine, naphthylene, orquinoline, in one embodiment, each of which is optionally substitutedwith one or more F, Cl, Br, cyano, methyl, ethyl, propyl, butyl, OH,OCH₃, CF₃, or OCF₃). In one embodiment, R³ and R⁴ together with theatoms to which they are attached form an optionally substitutedheterocyclyl ring (e.g., 2,3-dihydrobenzo[b][1,4]dioxine). Specificexamples include, but are not limited to, the following:

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein

wherein A² is NH, NCH₃, or O; each occurrence of R¹⁵ is independently:(i) hydrogen, halo, cyano, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴,—C(O)NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³,—S(O)₂R¹³, —S(O)₂NR¹³R¹⁴, (C₁-C₁₀)alkyl optionally substituted with oneor more R¹², (C₁-C₁₀)heteroalkyl optionally substituted with one or moreR¹², (C₃-C₁₀)cycloalkyl optionally substituted with one or more R¹²,(C₇-C₁₂)aralkyl optionally substituted with one or more R¹²,(C₃-C₁₂)heteroaralkyl optionally substituted with one or more R¹², (6 to10 membered)aryl optionally substituted with one or more R¹², (5 to 10membered)heteroaryl optionally substituted with one or more R¹², or (3to 12 membered)heterocyclyl optionally substituted with one or more R¹²;or (ii) when two occurrences of R¹⁵ are attached to adjacent carbonatoms, the two adjacent occurrences of R¹⁵ together with the carbonatoms to which they are attached may form a ring, optionally substitutedwith one or more R¹¹; wherein R¹¹, R¹², R¹³, and R¹⁴ are defined hereinelsewhere; and m is 0, 1, 2, 3, or 4. In one embodiment, L is —(CH₂)₂—or —CH═CH—. In one embodiment, each R¹⁵ is independently halo (e.g., F,Cl, or Br), cyano, methyl, ethyl, CF₃, OCH₃, or OCF₃. In one embodiment,two adjacent occurrences of R¹⁵ together with the carbon atoms to whichthey are attached form an optionally substituted phenyl. In oneembodiment, R³ is optionally substituted phenyl, pyridyl, furanyl,benzofuranyl, thienyl, benzodioxolyl, naphthyl, or quinolinyl (e.g.,optionally substituted with one or more F, Cl, Br, cyano, methyl, CF₃,or phenyl). In one embodiment, R⁴ is H. In one embodiment, R⁴ is phenyl.In one embodiment, A⁴ is NR⁵, and R⁵ is hydrogen or methyl. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform an optionally substituted aryl or heteroaryl (e.g., benzene,pyridine, naphthylene, or quinoline, in one embodiment, each of which isoptionally substituted with one or more F, Cl, Br, cyano, methyl, ethyl,propyl, butyl, OH, OCH₃, CF₃, or OCF₃). In one embodiment, A⁴ is O or S.Specific examples include, but are not limited to, the following:

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

A is

wherein R¹, R², A¹ and A² are defined herein elsewhere. In oneembodiment, A is optionally substituted phenyl or naphthyl. In oneembodiment, A is optionally substituted isoquinolinyl. In oneembodiment, A is optionally substituted isoquinolin-1(2H)-onyl. In oneembodiment, L is —(CH₂)₂— or —CH═CH—. In one embodiment, B is optionallysubstituted phenylimidazolyl. Specific examples include, but are notlimited to, the following:

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein R³, R⁴, and A⁵ are defined herein elsewhere. In one embodiment,A⁵ is CH. In one embodiment, R³ is phenyl and R⁴ is H. In oneembodiment, A⁵ is N. In one embodiment, R³ is H and R⁴ is pyridyl. Inone embodiment, specific examples include, but are not limited to, thefollowing:

In one embodiment, A⁵ is N. In one embodiment, A⁵ is CR⁵. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform an optionally substituted ring. In one embodiment, R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted 9- to 10-membered heteroaryl ring (i.e., B is an optionallysubstituted 12- to 13-membered heteroaryl).

In one embodiment, A⁵ is CH. In one embodiment, R⁴ is hydrogen. In oneembodiment, R³ is alkyl, aryl, or heteroaryl, each of which isoptionally substituted with one or more R¹¹.

In one embodiment, A⁵ is N. In one embodiment, R³ is hydrogen. In oneembodiment, R⁴ is alkyl, aryl, or heteroaryl, each of which isoptionally substituted with one or more R¹¹.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein R³, R⁴, and A⁵ are defined herein elsewhere.

In one embodiment, A⁵ is N. In one embodiment, R³ and R⁴ together withthe atoms to which they are attached form an optionally substitutedring. In one embodiment, R³ and R⁴ together with the atoms to which theyare attached form an optionally substituted 9- to 10-membered heteroarylring (i.e., B is an optionally substituted 12- to 13-memberedheteroaryl).

In one embodiment, A⁵ is CR⁵. In one embodiment, R⁵ is H or CH₃. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform an optionally substituted ring. In one embodiment, R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted pyridyl ring. In one embodiment, A is an optionallysubstituted 6- to 10-membered ring (e.g., quinoxalinyl or quinolinyl)(examples of optional substituents are provided herein elsewhere).Specific examples include, but are not limited to, the following:

In one embodiment, A⁵ is CR⁵. In one embodiment, R⁵ is H, halo, CH₃,cycloalkyl (e.g., cyclopropyl), or heterocyclyl (e.g., pyrrolidinyl,piperidinyl, piperazinyl, or morpholinyl) In one embodiment, R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted pyrimidinyl, pyrazinyl, or pyridazinyl ring. In oneembodiment, A is an optionally substituted 6- to 10-membered ring (e.g.,pyrimidinyl, pyridylpyrimidyl, quinoxalinyl, or quinolinyl) (examples ofoptional substituents are provided herein elsewhere). Specific examplesinclude, but are not limited to, the following:

In one embodiment, A⁵ is CR⁵. In one embodiment, R⁵ is H or CH₃. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform a 9- to 10-membered heteroaryl ring (e.g., a 9- to 10-memberedheteroaryl ring having 1, 2, or 3 nitrogen ring atoms). In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform a 10-membered heteroaryl ring having at least two nitrogen ringatoms (e.g., 2, 3, or 4 nitrogen ring atoms). In one embodiment, L is—(CH₂)₂ or CH═CH. In one embodiment, L is —O—CH₂— or —CH₂—O—. In oneembodiment, A is an optionally substituted 6- to 10-membered heteroarylring. In one embodiment, A is pyridyl, pyrimidyl, pyrazinyl,pyridylpyrimidyl, quinazolinyl, 6,7-dihydro-5H-cyclopenta[d]pyrimidinyl,dihydro-naphthyridinonyl, tetrahydro-naphthyridinyl, quinoxalinyl,quinolinyl, or naphthyridinyl, each of which is optionally substituted(e.g., with one or more halo, e.g., F, Cl, or Br, cyano, methyl, ethyl,CF₃, OCH₃, OCF₃, or heterocyclyl, e.g., pyrrolidinyl). In oneembodiment, A is quinoxalinyl, quinolinyl, or naphthyridinyl, each ofwhich is optionally substituted with one or more halo (e.g., F, Cl, orBr), cyano, methyl, ethyl, CF₃, OCH₃, or OCF₃. Specific examplesinclude, but are not limited to, the following:

In one embodiment, A⁵ is CR⁵. In one embodiment, R⁵ is H, halo, CH₃,cycloalkyl (e.g., cyclopropyl), or heterocyclyl (e.g., pyrrolidinyl,piperidinyl, piperazinyl, or morpholinyl). In one embodiment, R³ and R⁴together with the atoms to which they are attached form a 9- to10-membered heteroaryl or heterocyclyl ring (e.g., a 9- to 10-memberedring having 1, 2, 3, or 4 hetero atoms, such as one or more N, O, and/orS). Specific examples include, but are not limited to, the following:

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein each occurrence of R¹¹ may be the same or different, and isdefined herein elsewhere. In one embodiment, two adjacent occurrences ofR¹¹ together with the atoms to which they are attached form anoptionally substituted 5- or 6-membered aryl or heteroaryl (e.g.,phenyl, thienyl, pyridyl, pyrimidyl, or pyrazinyl ring, in oneembodiment, optionally substituted with one or more F, Cl, cyano,methyl, OCH₃, CF₃, or OCF₃). In one embodiment, the other twooccurrences of R¹¹ is H, halo (e.g., F, Cl, or Br), cyano, or methyl. Inone embodiment, L is —(CH₂)₂— or —CH═CH—. In one embodiment, A is anoptionally substituted 6- to 10-membered heteroaryl or heterocyclylring. In one embodiment, A is an optionally substituted 10-memberedheteroaryl or heterocyclyl ring. In one embodiment, A is pyridyl,pyrimidyl, pyrazinyl, pyridylpyrimidyl, quinazolinyl,6,7-dihydro-5H-cyclopenta[d]pyrimidinyl, dihydro-naphthyridinonyl,tetrahydro-naphthyridinyl, quinoxalinyl, quinolinyl, or naphthyridinyl,each of which is optionally substituted (e.g., with one or more halo,e.g., F, Cl, or Br, cyano, methyl, ethyl, CF₃, OCH₃, or OCF₃). In oneembodiment, A is quinoxalinyl, quinolinyl, or naphthyridinyl, each ofwhich is optionally substituted with one or more halo (e.g., F, Cl, orBr), cyano, methyl, ethyl, CF₃, OCH₃, or OCF₃. Specific examplesinclude, but are not limited to, the following:

In one embodiment, A⁵ is CH. In one embodiment, R⁴ is hydrogen ormethyl. In one embodiment, R³ is alkyl, aryl, or heteroaryl, each ofwhich is optionally substituted with one or more R¹¹

In one embodiment, A⁵ is N. In one embodiment, R⁴ is hydrogen. In oneembodiment, R³ is alkyl, aryl, or heteroaryl, each of which isoptionally substituted with one or more R¹¹.

In one embodiment, A⁵ is N or CH. In one embodiment, A⁵ is CH. In oneembodiment, R³ and R⁴ together with the atoms to which they are attachedform a pyridyl ring, which is optionally substituted with one or moreR¹¹.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein R³, R⁴, and A⁶ are defined herein elsewhere. In one embodiment,B is optionally substituted pyridyl (e.g., pyridyl optionallysubstituted with phenyl). In one embodiment, B is optionally substitutedquinoxalinyl, quinolinyl, or phenanthrolinyl. In one embodiment, A isquinoxalinyl, quinolinyl, or naphthyridinyl, each of which is optionallysubstituted with one or more halo (e.g., F, Cl, or Br), cyano, methyl,ethyl, CF₃, OCH₃, or OCF₃. In one embodiment, L is —(CH₂)₂— or —CH═CH—.Specific examples include, but are not limited to, the following:

In one embodiment, A⁶ is CH. In one embodiment, A⁶ is N. In oneembodiment, R⁴ is hydrogen. In one embodiment, R³ is alkyl, aryl, orheteroaryl, each of which is optionally substituted with one or moreR¹¹.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein A, L, R³, R⁴, and R⁵ are defined herein elsewhere. In oneembodiment, L is —(CH₂)₂— or —CH═CH—. In one embodiment, A isquinazolin-4(3H)-onyl. In one embodiment, B is thienyl substituted withphenyl. Specific examples include, but are not limited to, thefollowing:

In one embodiment, R⁴ is hydrogen. In one embodiment, R⁵ is hydrogen. Inone embodiment, R³ is alkyl, aryl, or heteroaryl, each of which isoptionally substituted with one or more R¹¹.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein R³, R⁴, and R¹⁹ are defined herein elsewhere. In one embodiment,B is phenylimidazolyl. In one embodiment, L is —(CH₂)₂— or —CH═CH—. Inone embodiment, A is quinazolin-4(3H)-onyl. Specific examples include,but are not limited to, the following:

In one embodiment, R⁴ is hydrogen. In one embodiment, R³ is alkyl, aryl,or heteroaryl, each of which is optionally substituted with one or moreR¹¹. In one embodiment, R¹⁹ is hydrogen.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein R³ and R⁴ are defined herein elsewhere. In one embodiment, B isphenylisoxazolyl. In one embodiment, L is —(CH₂)₂— or —CH═CH—. In oneembodiment, A is quinazolin-4(3H)-onyl. Specific examples include, butare not limited to, the following:

In one embodiment, R⁴ is hydrogen. In one embodiment, R³ is alkyl, aryl,or heteroaryl, each of which is optionally substituted with one or moreR¹¹.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein R⁴, R¹⁹, and A⁴ are defined herein elsewhere. In one embodiment,B is phenyloxazolyl. In one embodiment, L is —(CH₂)₂ or —CH═CH—. In oneembodiment, A is quinoxalinyl. Specific examples include, but are notlimited to, the following:

In one embodiment, R⁴ is alkyl, aryl, or heteroaryl, each of which isoptionally substituted with one or more R¹¹. In one embodiment, R¹⁹ ishydrogen. In one embodiment, A⁴ is O.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein B is

wherein R³, R⁴, and R²⁰ are defined herein elsewhere. In one embodiment,B is phenyl-1H-pyrazolyl, optionally substituted with methyl. In oneembodiment, L is —(CH₂)₂— or —CH═CH—. In one embodiment, A isquinazolin-4(3H)-onyl. Specific examples include, but are not limitedto, the following:

In one embodiment, R²⁰ is hydrogen or methyl. In one embodiment, R⁴ ishydrogen. In one embodiment, R³ is alkyl, aryl, or heteroaryl, each ofwhich is optionally substituted with one or more R¹¹.

In one embodiment, provided herein is a compound of formula (I):A-L-B   (I),or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

A is

and

L, B, R¹, and R² are defined herein elsewhere. In one embodiment, L is—(CH₂)₂— or —CH═CH—. In one embodiment, B is phenylimidazolyl. Specificexamples include, but are not limited to, the following:

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein

wherein each occurrence of R¹⁵ is independently: (i) hydrogen, halo,cyano, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³,—C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³, —S(O)₂R¹³, —S(O)₂NR¹³R¹⁴,(C₁-C₁₀)alkyl optionally substituted with one or more R¹²,(C₁-C₁₀)heteroalkyl optionally substituted with one or more R¹²,(C₃-C₁₀)cycloalkyl optionally substituted with one or more R¹²,(C₇-C₁₂)aralkyl optionally substituted with one or more R¹²,(C₃-C₁₂)heteroaralkyl optionally substituted with one or more R¹², (6 to10 membered)aryl optionally substituted with one or more R¹², (5 to 10membered) heteroaryl optionally substituted with one or more R¹², or (3to 12 membered)heterocyclyl optionally substituted with one or more R¹²;or (ii) when two occurrences of R¹⁵ are attached to adjacent carbonatoms, the two adjacent occurrences of R¹⁵ together with the carbonatoms to which they are attached may form a ring, optionally substitutedwith one or more R¹¹; wherein R¹¹, R¹², R¹³, and R¹⁴ are defined hereinelsewhere; and m is 0, 1, 2, 3, or 4.

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein

wherein each occurrence of R¹⁵ is independently: (i) hydrogen, halo,cyano, —OR¹³, —NR¹³R¹⁴, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³,—C(O)OR¹³, —OC(O)R¹³, —SR¹³, —S(O)R¹³, —S(O)₂R¹³, —S(O)₂NR¹³R¹⁴,(C₁-C₁₀)alkyl optionally substituted with one or more R¹²,(C₁-C₁₀)heteroalkyl optionally substituted with one or more R¹²,(C₃-C₁₀)cycloalkyl optionally substituted with one or more R¹²,(C₇-C₁₂)aralkyl optionally substituted with one or more R¹²,(C₃-C₁₂)heteroaralkyl optionally substituted with one or more R¹², (6 to10 membered)aryl optionally substituted with one or more R¹², (5 to 10membered) heteroaryl optionally substituted with one or more R¹², or (3to 12 membered)heterocyclyl optionally substituted with one or more R¹²;or (ii) when two occurrences of R¹⁵ are attached to adjacent carbonatoms, the two adjacent occurrences of R¹⁵ together with the carbonatoms to which they are attached may form a ring, optionally substitutedwith one or more R¹¹; wherein R¹¹, R¹², R¹³, and R¹⁴ are defined hereinelsewhere; and m is 0, 1, 2, 3, or 4.

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein

wherein R¹, R², and R⁸ are defined herein elsewhere, and A¹ is N or CR⁸.In one embodiment, each occurrence of R⁸ may be the same or different.In one embodiment, A¹ is N or CH. In one embodiment, R⁸ is hydrogen. Inone embodiment, R¹ and R² together with the carbon atoms to which theyare attached form an optionally substituted phenyl ring. In oneembodiment, R¹ and R² together with the carbon atoms to which they areattached form an optionally substituted pyridyl ring.

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein

wherein R¹, R², and R⁸ are defined herein elsewhere. In one embodiment,the two occurrences of R⁸ may be the same or different. In oneembodiment, R¹ and R² are hydrogen. In one embodiment, R¹ and R²together with the carbon atoms to which they are attached form anoptionally substituted phenyl ring. In one embodiment, R¹ and R²together with the carbon atoms to which they are attached form anoptionally substituted pyridyl ring.

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein

wherein R¹ and R⁸ are defined herein elsewhere; each occurrence of R¹⁶is independently R¹¹; wherein R¹¹ is defined herein elsewhere; and n is0, 1, 2, 3, 4, or 5.

In one embodiment, provided herein is a compound of formula (I) orformula (I-A), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein

wherein A⁷, A⁸ and A⁹ are each independently O, S, N, CR¹⁷, or NR¹⁸,wherein A⁷, A⁸ and A⁹ together with the two carbon atoms to which theyare attached form a stable five-membered heteroaryl ring (e.g., aheteroaryl ring provided herein elsewhere); each occurrence of R¹⁷ isindependently R¹¹; each occurrence of R¹¹ is hydrogen, —C(O)NR¹³R¹⁴,—C(O)R¹³, —C(O)OR¹³, —S(O)₂R¹³, (C₁-C₁₀)alkyl optionally substitutedwith one or more R¹², (C₁-C₁₀)heteroalkyl optionally substituted withone or more R¹², (C₃-C₁₀)cycloalkyl optionally substituted with one ormore R¹², (C₇-C₁₂)aralkyl optionally substituted with one or more R¹²,(C₃-C₁₂)heteroaralkyl optionally substituted with one or more R¹², (6 to10 membered)aryl optionally substituted with one or more R¹², (5 to 10membered)heteroaryl optionally substituted with one or more R¹², or (3to 12 membered)heterocyclyl optionally substituted with one or more R¹²;wherein R¹¹, R¹², R¹³ and R¹⁴ are as defined herein elsewhere.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein R³ are defined herein elsewhere. In one embodiment, R³ is alkyl,aryl, or heteroaryl, each of which is optionally substituted with one ormore R¹¹.

In one embodiment, provided herein is a compound of formula (I), or apharmaceutically acceptable salt or stereoisomer thereof, wherein

B is

wherein R¹¹ is defined herein elsewhere. In one embodiment, eachoccurrence of R¹¹ may be the same or different from each other.

Any of the combinations of A, B, L, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R⁸, R¹⁹, R²⁰, A¹, A², A³, A⁴,A⁵, A⁶, A⁷, A⁸, A⁹, m, n, k, G, J, u, p, and q are encompassed by thisdisclosure and specifically provided herein.

In one embodiment, provided herein is a compound of formula (I-B):D-L-E   (I-B),or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

L is —(CH₂)_(u), —CH═CH—, or —(CH₂)_(p)—S—(CH₂)_(q)—;

D is

E is

X is N or CR²⁶;

each Y is independently N or CR;

each Z is independently N or C;

Q is independently N or CR²⁵;

provided that D contains 1, 2, 3, or 4 nitrogen ring atoms;

each occurrence of R is independently hydrogen, halo, cyano,(C₁-C₆)alkyl, (C₁-C₆)alkoxyl, (C₁-C₆)hydroxyalkyl, aryl, or heteroaryl;each of which is optionally substituted;

R²⁵ is hydrogen, halo, cyano, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₁-C₆)alkoxyl, (C₁-C₆)hydroxyalkyl, CH₂CN, CH₂C(O)NH₂, (C₇-C₁₂)aralkyl,or alkyl-heterocycloalkyl; each of which is optionally substituted;

R²⁶ and R²⁷ are independently hydrogen, halo, cyano, (C₁-C₆)alkyl,(C₁-C₆)alkoxyl, aryl, or heteroaryl; each of which is optionallysubstituted; or R²⁶ and R²⁷ together with the atoms to which they areattached form an optionally substituted cycloalkyl, aryl, heteroaryl, orheterocyclyl ring;

u is 2 or 3; and

p and q are each independently 0, 1, or 2, provided that when one of pand q is 0, the other is 1 or 2.

In one embodiment, L is —(CH₂)_(u)—. In one embodiment, L is —CH═CH—. Inone embodiment, L is —(CH₂)_(p)—S—(CH₂)_(q)—.

In one embodiment, u is 2. In one embodiment, u is 3.

In one embodiment, p is 0. In one embodiment, p is 1. In one embodiment,p is 2. In one embodiment, q is 0. In one embodiment, q is 1. In oneembodiment, q is 2. In one embodiment, when p is 0, q is 1 or 2. In oneembodiment, when q is 0, p is 1 or 2. In one embodiment, L is —CH₂—CH₂—,—CH₂—CH₂—CH₂—, —S—CH₂—, —CH₂—S—, —CH═CH—, —S—CH₂—CH₂—, —CH₂—S—CH₂—, or—CH₂—CH₂—S—. In one embodiment, L is —CH₂—CH₂—. In one embodiment, L is—CH₂—CH₂—CH₂—. In one embodiment, L is —S—CH₂—. In one embodiment, L is—CH₂—S—. In one embodiment, L is —CH═CH—. In one embodiment, L is—S—CH₂—CH₂—. In one embodiment, L is —CH₂—S—CH₂—. In one embodiment, Lis —CH₂—CH₂—S—. In one embodiment, L is —CH₂—CH₂—, —CH₂—CH₂—CH₂—, or—CH═CH—. In one embodiment, D contains from 1 to 2, from 1 to 3, from 1to 4, from 2 to 3, from 2 to 4, or from 3 to 4 nitrogen ring atoms. Inone embodiment, D contains one nitrogen ring atom. In one embodiment, Dcontains two nitrogen ring atoms. In one embodiment, D contains threenitrogen ring atoms. In one embodiment, D contains four nitrogen ringatoms.

In one embodiment, D is:

wherein Y is defined herein elsewhere.

In one embodiment, D is:

wherein Y is defined herein elsewhere.

In one embodiment, D is:

wherein R and Y are defined herein elsewhere.

In one embodiment, R is halo, cyano, (C₁-C₆)alkyl, (C₁-C₆)alkoxyl,(C₁-C₆)hydroxyalkyl, aryl, or heteroaryl; each of which is optionallysubstituted. In one embodiment, R is halo, cyano, (C₁-C₆)alkyl, or(C₁-C₆)alkoxyl, each of which is optionally substituted.

In one embodiment, D is:

wherein R is defined herein elsewhere.

In one embodiment, D is optionally substituted with up to threesubstituents. In one embodiment, up to three occurrences of Rsubstituting D are not hydrogen.

In one embodiment, D is:

wherein R is defined herein elsewhere.

In one embodiment, each occurrence of R is independently hydrogen ormethyl.

In one embodiment, D is:

In one embodiment, E contains from 1 to 2, from 1 to 3, from 1 to 4,from 2 to 3, from 2 to 4, or from 3 to 4 nitrogen ring atoms. In oneembodiment, E contains one nitrogen ring atom. In one embodiment, Econtains two nitrogen ring atoms. In one embodiment, E contains threenitrogen ring atoms. In one embodiment, E contains four nitrogen ringatoms.

In one embodiment, E is optionally substituted with up to one, up totwo, up to three, up to four, or up to five substituents.

In one embodiment, E is:

wherein Q, Y, R²⁶, and R²⁷ are defined herein elsewhere.

In one embodiment, E is:

wherein Y and R²⁵ are defined herein elsewhere;

Y¹ is N or CR²¹; Y² is N or CR²²; Y³ is N or CR²³; and Y⁴ is N or CR²⁴;provided that at least one of Y¹, Y², Y³, and Y⁴ is not N;

Z¹ is N, O, S, CR²¹, or NR²¹; Z² is N, O, S, CR²², or NR²²; and Z³ is N,O, S, CR²³, or NR²³; provided that Z¹, Z², and Z³ together with thecarbon atoms to which they are attached form a stable 5-memberedheteroaryl;

each occurrence of R²¹, R²², R²³, and R²⁴ is independently hydrogen,halo, cyano, (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl,(C₁-C₆)heteroalkyl, (C₁-C₆)alkoxyl, (C₁-C₆)aminoalkyl,(C₁-C₆)hydroxyalkyl, CH₂CN, CH₂C(O)NH₂, (C₃-C₈)cycloalkyl, aryl,heteroaryl, heterocyclyl, aralkyl, heteroaralkyl, oralkyl-heterocycloalkyl; each of which is optionally substituted; and

two adjacent R²¹, R²², R²³, and R²⁴ may together with the atoms to whichthey are attached form an optionally substituted aromatic ornon-aromatic ring.

In one embodiment, one of Y¹, Y², Y³, and Y⁴ is N, and the other threeare carbon (e.g., CR²¹, CR²², CR²³, or CR²⁴). In one embodiment, two ofY¹, Y², Y³, and Y⁴ are N, and the other two are carbon (e.g., CR²¹,CR²², CR²³, or CR²⁴). In one embodiment, three of Y¹, Y², Y³, and Y⁴ areN, and the other one is carbon (e.g., CR²¹, CR²², CR²³, or CR²⁴). In oneembodiment, Y¹, Y², Y³, and Y⁴ are all carbon (e.g., CR²¹, CR²², CR³, orCR²⁴).

In one embodiment, E is:

wherein Y, R²¹, R²², R²³, R²⁴, and R²⁵ are defined herein elsewhere.

In one embodiment, E is:

wherein R, R²¹, R²², R²³, R²⁴, and R²⁵ are defined herein elsewhere. Insome embodiments, R is hydrogen. In some embodiments, R²¹, R²², R²³,R²⁴, and R²⁵ are each independently hydrogen, halo (e.g., fluoro orchloro), cyano, (C₁-C₄)alkyl (e.g., methyl or CF₃), or (C₁-C₄)alkoxyl(e.g., methoxyl or OCF₃). In some embodiments, R²¹ and R²², R²² and R²³,or R²³ and R²⁴ together with the carbon atoms to which they are attachedform an optionally substituted ring, such as, e.g., a benzene, pyridine,pyrimidine, pyrazine, pyridazine, thiophene, furan, pyrrole, imidazole,pyrazole, oxazole, isoxazole, thiazole, or isothiazole ring; or a 5- to7-membered non-aromatic carbocyclic or heterocyclic ring, wherein thenon-aromatic heterocyclic ring contains one to two heteroatom(s)independently selected from N, O, and S.

In one embodiment, E is not:

In one embodiment, E is:

wherein R, R²¹, R²², R²³, R²⁴, and R²⁵ are defined herein elsewhere. Insome embodiments, R is hydrogen. In some embodiments, R²¹, R²², R²³,R²⁴, and R²⁵ are each independently hydrogen, halo (e.g., fluoro orchloro), cyano, (C₁-C₄)alkyl (e.g., methyl or CF₃), or (C₁-C₄)alkoxyl(e.g., methoxyl or OCF₃). In some embodiments, R²¹ and R²², R²² and R²³,or R²³ and R²⁴ together with the carbon atoms to which they are attachedform an optionally substituted ring, such as, e.g., a benzene, pyridine,pyrimidine, pyrazine, pyridazine, thiophene, furan, pyrrole, imidazole,pyrazole, oxazole, isoxazole, thiazole, or isothiazole ring; or a 5- to7-membered non-aromatic carbocyclic or heterocyclic ring, wherein thenon-aromatic heterocyclic ring contains one to two heteroatom(s)independently selected from N, O, and S.

In one embodiment, E is:

wherein R, R²¹, R²², R²³, and R²⁵ are defined herein elsewhere. In someembodiments, R is hydrogen. In some embodiments, R²¹, R²², R²³, and R²⁵are each independently hydrogen, halo (e.g., fluoro or chloro), cyano,(C₁-C₄)alkyl (e.g., methyl or CF₃), or (C₁-C₄)alkoxyl (e.g., methoxyl orOCF₃). In some embodiments, R²¹ and R²², or R²² and R²³ together withthe carbon atoms to which they are attached form an optionallysubstituted ring, such as, e.g., a benzene, pyridine, pyrimidine,pyrazine, pyridazine, thiophene, furan, pyrrole, imidazole, pyrazole,oxazole, isoxazole, thiazole, or isothiazole ring; or a 5- to 7-memberednon-aromatic carbocyclic or heterocyclic ring, wherein the non-aromaticheterocyclic ring contains one to two heteroatom(s) independentlyselected from N, O, and S.

In one embodiment, X is CR²⁶. In one embodiment, X is N.

In one embodiment, Y is N. In one embodiment, Y is CR. In oneembodiment, Y is CH. In one embodiment, Y is CMe. One occurrence of Ymay be the same or different from another occurrence of Y.

In one embodiment, Z is N. In one embodiment, Z is C. One occurrence ofZ may be the same or different from another occurrence of Z. In oneembodiment, one of the two occurrences of Z is C and the other is N. Inone embodiment, one of the two occurrences of Z is N. In one embodiment,one of the two occurrences of Z is C. In one embodiment, at least one ofthe two occurrences of Z is N. In one embodiment, the two occurrences ofZ are not both C.

In one embodiment, the two occurrences of Z are not both N.

In one embodiment, Q is N. In one embodiment, Q is CR²⁵.

In one embodiment, R is hydrogen. In one embodiment, R is halo. In oneembodiment, R is cyano. In one embodiment, R is (C₁-C₆)alkyl. In oneembodiment, R is methyl. In one embodiment, R is (C₁-C₆)alkoxyl. In oneembodiment, R is (C₁-C₆) hydroxyalkyl. In one embodiment, R is aryl. Inone embodiment, R is heteroaryl. In one embodiment, R is not hydrogen.In one embodiment, R is halo, cyano, (C₁-C₆)alkyl, (C₁-C₆) alkoxyl,(C₁-C₆)hydroxyalkyl, aryl, or heteroaryl; each of which is optionallysubstituted. In one embodiment, R is a monovalent radical (e.g., twoadjacent occurrences of R do not together with the atoms to which theyare attached form a ring). Each occurrence of R may be optionallysubstituted. One occurrence of R may be the same or different fromanother occurrence of R.

In one embodiment, R²⁵ is hydrogen. In one embodiment, R²⁵ is halo. Inone embodiment, R²⁵ is cyano. In one embodiment, R²⁵ is (C₁-C₆)alkyl. Inone embodiment, R²⁵ is (C₃-C₈)cycloalkyl. In one embodiment, R²⁵ is(C₁-C₆)alkoxyl. In one embodiment, R²⁵ is (C₁-C₆)hydroxyalkyl. In oneembodiment, R²⁵ is CH₂CN. In one embodiment, R²⁵ is CH₂C(O)NH₂. In oneembodiment, R²⁵ is (C₇-C₁₂)aralkyl. In one embodiment, R²⁵ isalkyl-heterocycloalkyl. Each embodiment of R²⁵ may be optionallysubstituted.

In one embodiment, R²⁶ is hydrogen. In one embodiment, R²⁶ is halo. Inone embodiment, R²⁶ is cyano. In one embodiment, R²⁶ is (C₁-C₆)alkyl. Inone embodiment, R²⁶ is (C₁-C₆)alkoxyl. In one embodiment, R²⁶ is aryl.In one embodiment, R²⁶ is heteroaryl. Each embodiment of R²⁶ may beoptionally substituted.

In one embodiment, R²⁷ is hydrogen. In one embodiment, R²⁷ is halo. Inone embodiment, R²⁷ is cyano. In one embodiment, R²⁷ is (C₁-C₆)alkyl. Inone embodiment, R²⁷ is (C₁-C₆)alkoxyl. In one embodiment, R²⁷ is aryl.In one embodiment, R²⁷ is heteroaryl. Each embodiment of R²⁷ may beoptionally substituted.

In one embodiment, R²⁶ and R²⁷ together with the atoms to which they areattached form an optionally substituted aromatic or non-aromaticmonocyclic or multicyclic ring, including but not limited to, phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, thienyl,furanyl, pyrrolyl, quinolinyl, or benzothiophenyl ring. The ring may beoptionally substituted as defined herein elsewhere.

In one embodiment, R²¹ is hydrogen. In one embodiment, R²¹ is halo. Inone embodiment, R²¹ is cyano. In one embodiment, R²¹ is (C₁-C₆)alkyl. Inone embodiment, R²¹ is (C₂-C₆)alkenyl. In one embodiment, R²¹ is(C₂-C₆)alkynyl. In one embodiment, R²¹ is (C₁-C₆)heteroalkyl. In oneembodiment, R²¹ is (C₁-C₆)alkoxyl. In one embodiment, R²¹ is(C₁-C₆)aminoalkyl. In one embodiment, R²¹ is (C₁-C₆)hydroxyalkyl. In oneembodiment, R²¹ is CH₂CN. In one embodiment, R²¹ is CH₂C(O)NH₂. In oneembodiment, R²¹ is (C₃-C₈) cycloalkyl. In one embodiment, R²¹ is aryl.In one embodiment, R²¹ is heteroaryl. In one embodiment, R²¹ isheterocyclyl. In one embodiment, R²¹ is (C₇-C₁₂)aralkyl. In oneembodiment, R²¹ is heteroaralkyl. In one embodiment, R²¹ isalkyl-heterocycloalkyl. Each embodiment of R² may be optionallysubstituted.

In one embodiment, R²² is hydrogen. In one embodiment, R²² is halo. Inone embodiment, R²² is cyano. In one embodiment, R²² is (C₁-C₆)alkyl. Inone embodiment, R²² is (C₂-C₆)alkenyl. In one embodiment, R²² is(C₂-C₆)alkynyl. In one embodiment, R²² is (C₁-C₆)heteroalkyl. In oneembodiment, R²² is (C₁-C₆)alkoxyl. In one embodiment, R²² is(C₁-C₆)aminoalkyl. In one embodiment, R²² is (C₁-C₆)hydroxyalkyl. In oneembodiment, R²² is CH₂CN. In one embodiment, R²² is CH₂C(O)NH₂. In oneembodiment, R²² is (C₃-C₈) cycloalkyl. In one embodiment, R²² is aryl.In one embodiment, R²² is heteroaryl. In one embodiment, R²² isheterocyclyl. In one embodiment, R²² is (C₇-C₁₂)aralkyl. In oneembodiment, R²² is heteroaralkyl. In one embodiment, R²² isalkyl-heterocycloalkyl. Each embodiment of R²² may be optionallysubstituted.

In one embodiment, R²³ is hydrogen. In one embodiment, R²³ is halo. Inone embodiment, R²³ is cyano. In one embodiment, R²³ is (C₁-C₆)alkyl. Inone embodiment, R²³ is (C₂-C₆)alkenyl. In one embodiment, R²³ is(C₂-C₆)alkynyl. In one embodiment, R²³ is (C₁-C₆)heteroalkyl. In oneembodiment, R²³ is (C₁-C₆)alkoxyl. In one embodiment, R²³ is(C₁-C₆)aminoalkyl. In one embodiment, R²³ is (C₁-C₆)hydroxyalkyl. In oneembodiment, R²³ is CH₂CN. In one embodiment, R²³ is CH₂C(O)NH₂. In oneembodiment, R²³ is (C₃-C₈) cycloalkyl. In one embodiment, R²³ is aryl.In one embodiment, R²³ is heteroaryl. In one embodiment, R²³ isheterocyclyl. In one embodiment, R²³ is (C₇-C₁₂)aralkyl. In oneembodiment, R²³ is heteroaralkyl. In one embodiment, R²³ isalkyl-heterocycloalkyl. Each embodiment of R²³ may be optionallysubstituted.

In one embodiment, R²⁴ is hydrogen. In one embodiment, R²⁴ is halo. Inone embodiment, R²⁴ is cyano. In one embodiment, R²⁴ is (C₁-C₆)alkyl. Inone embodiment, R²⁴ is (C₂-C₆)alkenyl. In one embodiment, R²⁴ is(C₂-C₆)alkynyl. In one embodiment, R²⁴ is (C₁-C₆)heteroalkyl. In oneembodiment, R²⁴ is (C₁-C₆)alkoxyl. In one embodiment, R²⁴ is(C₁-C₆)aminoalkyl. In one embodiment, R²⁴ is (C₁-C₆)hydroxyalkyl. In oneembodiment, R²⁴ is CH₂CN. In one embodiment, R²⁴ is CH₂C(O)NH₂. In oneembodiment, R²⁴ is (C₃-C₈) cycloalkyl. In one embodiment, R²⁴ is aryl.In one embodiment, R²⁴ is heteroaryl. In one embodiment, R²⁴ isheterocyclyl. In one embodiment, R²⁴ is (C₇-C₁₂)aralkyl. In oneembodiment, R²⁴ is heteroaralkyl. In one embodiment, R²⁴ isalkyl-heterocycloalkyl. Each embodiment of R²⁴ may be optionallysubstituted.

In one embodiment, R²¹ and R²², R²² and R²³, or R²³ and R²⁴ togetherwith the atoms to which they are attached form an optionally substitutedaromatic or non-aromatic ring, including but not limited to, phenyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, thienyl,thiazolyl, or 5- or 6-membered heterocyclyl ring. Other embodiments ofthe optionally substituted aromatic or non-aromatic ring are providedherein elsewhere.

In one embodiment, provided herein is a compound of formula (II-A):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinY, R, u, R²⁵, Y¹, Y², Y³, and Y⁴ are defined herein elsewhere.

In one embodiment, provided herein is a compound of formula (II-B):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinY, R, u, R²⁵, Z¹, Z², and Z³ are defined herein elsewhere. In oneembodiment, Z² is CR²², and (i) Z¹ is S and Z³ is CR²³, or (ii) Z isCR²¹ and Z³ is S; wherein R²¹, R²², and R²³ are defined hereinelsewhere. In one embodiment, R is H or Me. In one embodiment, Y is N orCH. In one embodiment, R²¹, R²², and R²³ are H; or R²² and R²³, or R²¹and R²², together with the carbon atoms to which they are attached forman optionally substituted phenyl ring. Specific examples include, butare not limited to the following:

In one embodiment, provided herein is a compound of formula (III-A):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR, R²¹, R²², R²³, R²⁴, and R²⁵ are defined herein elsewhere. In oneembodiment, R is H or Me. In one embodiment, R²¹, R²², R²³, R²⁴, and R²⁵are each independently H, halo (e.g., F, Cl, or Br), methyl, or CF₃. Inone embodiment, R²³ and R²⁴ together with the carbon atoms to which theyare attached form an optionally substituted phenyl, pyridyl, pyrimidyl,pyrazinyl, tetrahydropyridinyl, or 3,4-dihydro-2H-1,4-oxazinyl ring.Specific examples include, but are not limited to:

In one embodiment, provided herein is a compound of formula (III-B):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR, R²¹, R²², R²³, R²⁴, and R²⁵ are defined herein elsewhere. In oneembodiment, R is H or Me. In one embodiment, R²¹, R²², R²³, R²⁴, and R²⁵are each independently H, halo (e.g., F, Cl, or Br), methyl, or CF₃.Specific examples include, but are not limited to:

In one embodiment, provided herein is a compound of formula (III-C):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR, Y¹, Y², Y³, Y⁴, and R²⁵ are defined herein elsewhere. In oneembodiment, at least one of Y¹, Y², Y³, and Y⁴ is N. In one embodiment,one of Y¹, Y², Y³, and Y⁴ is N and the other three of Y¹, Y², Y³, and Y⁴are substituted C as defined herein elsewhere. In one embodiment, R is Hor Me. In one embodiment, R²¹, R²², R²³, R²⁴, and R²⁵ are eachindependently H, halo (e.g., F, Cl, or Br), methyl, or CF₃. Specificexamples include, but are not limited to:

In one embodiment, provided herein is a compound of formula (III-D):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR, Y, R²¹, R²², R²³, R²⁴, and R²⁵ are defined herein elsewhere. In oneembodiment, R is H or Me. In one embodiment, Y is CH or N. In oneembodiment, R²¹, R²², R²³, R²⁴, and R²⁵ are each independently II, halo(e.g., F, Cl, or Br), methyl, or CF₃. Specific examples include, but arenot limited to:

In one embodiment, provided herein is a compound of formula (III-E):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR, Y, R²¹, R²², R²³, R²⁴, and R²⁵ are defined herein elsewhere. In oneembodiment, R is H or Me. In one embodiment, Y is N or CH. In oneembodiment, R²¹, R²², R²³, R²⁴, and R²⁵ are each independently H, halo(e.g., F, Cl, or Br), methyl, or CF₃. In one embodiment, R²³ and R²⁴together with the carbon atoms to which they are attached form anoptionally substituted phenyl, pyridyl, pyrazinyl, or pyrimidyl ring.Specific examples include, but are not limited to:

In one embodiment, provided herein is a compound of formula (III-F):

or a pharmaceutically acceptable salt or stereoisomer thereof, whereinR, Y, R²¹, R²², R²³, R²⁴, and R²⁵ are defined herein elsewhere. In oneembodiment, R is H or Me. In one embodiment, Y is N or CH. In oneembodiment, R²¹, R²², R²³, R²⁴, and R²⁵ are each independently H, halo(e.g., F, Cl, or Br), methyl, or CF₃. Specific examples include, but arenot limited to:

In one embodiment, the compound of formula (I-B) is not:

Any of the combinations of D, E, L, X, Y, Z, Y¹, Y², Y³, Y⁴, Z¹, Z², Z³,Q, R, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, u, p and q are encompassed bythis disclosure and specifically provided herein.

It should be noted that if there is a discrepancy between a depictedstructure and a chemical name given that structure, the depictedstructure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it. Where the compound provided herein contains analkenyl or alkenylene group, the compound may exist as one geometric(i.e., cis/trains) isomer or a mixture of geometric (i.e., cis/trans)isomers.

Where structural isomers are inter-convertible, the compound may existas a single tautomer or a mixture of tautomers. This can take the formof proton tautomerism in the compound that contains, for example, animino, keto, or oxime group; or so-called valence tautomerism in thecompound that contain, for example, an aromatic moiety. It follows thata single compound may exhibit more than one type of isomerism. Unlessotherwise specified, a structure is intended to encompass anycorresponding tautomeric forms.

Unless otherwise specified, the term “compound” referred to herein, suchas, e.g., a compound of formula (I), (I-A), (I-B), (II-A), (II-B),(III-A), (III-B), (III-C), (III-D), (III-E), or (III-F) is intended toencompass one or more of the following: a free base of the compound or asalt thereof, a stereoisomer or a mixture of two or more stereoisomers,a solid form (e.g., a crystal form or an amorphous form) or a mixture oftwo or more solid forms thereof, or a solvate (e.g., a hydrate) thereof.In certain embodiments, the term “compound” referred to herein isintended to encompass a pharmaceutical acceptable form of the compound,including but not limited to, a free base, a pharmaceutically acceptablesalt, a stereoisomer or a mixture of two or more stereoisomers, a solidform (e.g., a crystal form or an amorphous form) or a mixture of two ormore solid forms, a solvate (e.g., a hydrate), or a cocrystal thereof.In one embodiment, the term “compound” referred to herein, such as,e.g., a compound of formula (I), (I-A), (I-B), (II-A), (II-B), (III-A),(III-B), (III-C), (III-D), (III-E), or (III-F) is intended to encompassa solvate (e.g., a hydrate) thereof.

The compounds provided herein may be enantiomerically pure, such as asingle enantiomer or a single diastereomer, or be stereoisomericmixtures, such as a mixture of enantiomers, e.g., a racemic mixture oftwo enantiomers; or a mixture of two or more diastereomers. In someinstances, for compounds that undergo epimerization in vivo, one ofskill in the art will recognize that administration of a compound in its(R) form is equivalent to administration of the compound in its (S)form, and vice versa. Conventional techniques for thepreparation/isolation of individual enantiomers include synthesis from asuitable optically pure precursor, asymmetric synthesis from achiralstarting materials, or resolution of an enantiomeric mixture, forexample, by chiral chromatography, recrystallization, resolution,diastereomeric salt formation, or derivatization into diastereomericadducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, boric acid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamicacid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonicacid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid,D-glucuronic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,(+)-L-lactic acid, (+)-DL-lactic acid, lactobionic acid, lauric acid,maleic acid, (−)-L-malic acid, malonic acid, (±)-DL-mandelic acid,methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinicacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid,saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid,stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaricacid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, andvaleric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, orsodium hydroxide; and organic bases, such as primary, secondary,tertiary, and quaternary, aliphatic and aromatic amines, includingL-arginine, benethamine, benzathine, choline, deanol, diethanolanine,diethylanine, dimethylanmine, dipropylamine, diisopropylamine,2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine,isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine,morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine,piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine,pyridine, quinuclidine, quinoline, isoquinoline, secondary amines,triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula I, andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzyinol. 1985, 112, 360-381; Farquhar et al., J. Pharmn. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakkcr, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

In one embodiment, the compounds provided herein are modulators of a PDEenzyme. In one embodiment, the compounds provided herein are inhibitorsof a PDE enzyme. In one embodiment, the compounds provided herein areinhibitors of PDE-10. In one embodiment, the compounds provided hereinare inhibitors of PDE-10A. In one embodiment, the compounds providedherein are selective inhibitors of PDE-10. In one embodiment, thecompounds provided herein are selective inhibitors of PDE-10A. In oneembodiment, the compounds provided herein are active in one or moreanimal models for a disorder provided herein elsewhere. In oneembodiment, the compounds provided herein are active in one or moreanimal models for a CNS disorder provided herein elsewhere. In oneembodiment, the compounds provided herein are active in one or moreanimal models for psychosis, schizophrenia, or antipsychotic activity,including without limitation, the conditioned avoidance response (CAR)assay, and any other animal models for psychosis, schizophrenia orantipsychotic activity that are known in the art. In one embodiment, thecompounds provided herein are active in one or more animal models forpsychosis, schizophrenia, or antipsychotic activity, including but notlimited to, conditioned avoidance response (CAR), pre-pulse inhibition(PPI), PCP-induced hyperlocomotion, and other animal models providedherein elsewhere. In one embodiment, compounds that are active in invitro assays (e.g., PDE-10A inhibition) or in vivo models for psychosis,schizophrenia or antipsychotic activity (e.g., CAR) are furtheroptimized to improve the potency in in vitro and in vivo assays anddrug-like properties such as, e.g., solubility and lipophilicity. In oneembodiment, the compounds provided herein are useful for treating,preventing, or ameliorating one or more symptoms of schizophrenia,including, positive, negative, and cognitive symptoms. In oneembodiment, the compounds provided herein induce fewer side effects,such as weight gain, in a subject treated with the compound. In oneembodiment, the compounds provided herein induce fewer side effects,such as extrapyramidal side effects, in a subject treated with thecompound. In one embodiment, the compounds provided herein are active inone or more animal models for obesity, undesirable weight retention orweight gain, metabolic syndrome, diabetes, non-insulin dependentdiabetes, impaired glucose tolerance, or hyperglycemia, includingwithout limitation, in vivo glucose tolerance test (GTT), diet-inducedobesity model, obesity food intake model, and any other animal modelsknown in the art or provided herein elsewhere. In one embodiment,compounds that are active in in vitro assays (e.g., PDE-10A inhibition)or in vivo models for obesity, undesirable weight retention or weightgain, metabolic syndrome, diabetes, non-insulin dependent diabetes,impaired glucose tolerance, or hyperglycemia are further optimized toimprove the potency in in vitro and in vivo assays and drug-likeproperties such as, e.g., solubility and lipophilicity.

C. Synthetic Schemes

Schemes below provide exemplary synthetic methods for the preparation ofthe compounds provided herein. One of ordinary skills in the art willunderstand that similar methods may be employed to prepare the compoundsprovided herein. In other words, one of ordinary skills in the art willrecognize that suitable adjustments to reagents, protecting groups,reaction conditions, and reaction sequences may be employed to prepare adesired embodiment.

The reactions may be scaled upwards or downwards to suit the amount ofmaterial to be prepared.

In one embodiment, the compound of formula (I) may be prepared followingSchemes 1-8, using suitable starting materials known in the art and/oravailable from a commercial source. In one embodiment, the startingmaterials of Scheme 1-8 may be prepared from commercially availablecompounds using procedures and conditions known in the art.

In one embodiment, a suitable triphenylphosphine halide is reacted witha suitable aldehyde or ketone in the presence of a base to render asubstituted ethylene (Scheme 1), which may be further reduced (e.g., byhydrogenation) to render a substituted ethane compound as shown inScheme 1. In one embodiment, Ar¹ or Ar² may be further converted toother suitable embodiments of Ar¹ or Ar² (e.g., transformation ofsubstitution groups) using procedures and conditions known in the art.

In one embodiment, a suitable Ar¹—CH₃ is reacted with a suitablealdehyde in the presence of acid (e.g., acetic acid, zinc chloride,heating) to render a substituted ethylene (Scheme 2), which may befurther reduced (e.g., by hydrogenation) to render a substituted ethanecompound as shown in Scheme 2. In one embodiment, Ar¹ or Ar² may befurther converted to other suitable embodiments of Ar¹ or Ar² (e.g.,transformation of substitution groups) using procedures and conditionsknown in the art.

In another embodiment, a suitable Ar¹—CH₃ is reacted with a suitablealdehyde in the presence of acid (e.g., acetic acid, heating) to rendera substituted hydroxylethylene compound (Scheme 3), which is convertedto the corresponding chloride (e.g., using SOCl₂) and reduced (e.g.,using Pd on Carbon) to render a substituted ethane compound as shown inScheme 3. In one embodiment, Ar¹ or Ar² may be further converted toother suitable embodiments of Ar¹ or Ar² (e.g., transformation ofsubstitution groups) using procedures and conditions known in the art.

In one embodiment, a suitable substituted diaminoaryl or substituteddiaminoheteroaryl is reacted with a suitable substituted propionic acidunder amide coupling conditions to yield the corresponding amide (Scheme4), which is cyclized under acidic condition (e.g., acetic acid) torender a substituted ethyl-imidazole compound as shown in Scheme 4. Inone embodiment, the diaminoaryl or diaminoheteroaryl compound issubstituted with one or more R, a suitable substituent, which may be thesame or different. In one embodiment, Ar or R may be further convertedto other suitable embodiments of Ar or R (e.g., transformation ofsubstitution groups) using procedures and conditions known in the art.In one embodiment, the imidazole ring may be further alkylated to renderan N-substituted imidazole compound.

In one embodiment, a suitable substituted aminothioaryl or substitutedaminothioheteroaryl is reacted with a suitable substituted propionicacid under amide coupling conditions to yield the corresponding amide(Scheme 5), which is cyclized under acidic condition (e.g., PPA) torender a substituted ethyl-thiazole compound as shown in Scheme 5. Inone embodiment, the aminothioaryl or aminothioheteroaryl compound issubstituted with one or more R, a suitable substituent, which may be thesame or different. In one embodiment, Ar or R may be further convertedto other suitable embodiments of Ar or R (e.g., transformation ofsubstitution groups) using procedures and conditions known in the art.

In one embodiment, a suitable heteroaryl chloride is reacted with asuitable substituted hydroxymethyl compound in the presence of base toyield the corresponding heteroaryl ether compound as shown in Scheme 6.In one embodiment, HetAr or Ar may be further converted to othersuitable embodiments of HetAr or Ar (e.g., transformation ofsubstitution groups) using procedures and conditions known in the art.

In one embodiment, a suitable heteroaryl chloride is reacted with asuitable substituted thioaryl or thioheteroaryl compound in the presenceof base to yield the corresponding heteroaryl thioether compound asshown in Scheme 7. In one embodiment, HetAr or Ar may be furtherconverted to other suitable embodiments of HetAr or Ar (e.g.,transformation of substitution groups) using procedures and conditionsknown in the art.

In one embodiment, a suitable heteroaryl chloride is reacted with asuitable substituted aminomethyl compound in the presence of base toyield the corresponding aminoheteroaryl compound as shown in Scheme 8.In one embodiment, HetAr or Ar may be further converted to othersuitable embodiments of HetAr or Ar (e.g., transformation ofsubstitution groups) using procedures and conditions known in the art.

In other embodiments, the compounds provided herein may be preparedusing the general procedures described herein below. In one embodiment,the compounds provided herein may be prepared using General Procedure A.In one embodiment, the compounds provided herein may be prepared usingGeneral Procedure B. In one embodiment, the compounds provided hereinmay be prepared using General Procedure C. In one embodiment, thecompounds provided herein may be prepared using General Procedure D. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure E. In one embodiment, the compounds provided hereinmay be prepared using General Procedure F. In one embodiment, thecompounds provided herein may be prepared using General Procedure G.

In one embodiment, the compounds provided herein may be prepared usingGeneral Procedure H. In one embodiment, the compounds provided hereinmay be prepared using General Procedure I. In one embodiment, thecompounds provided herein may be prepared using General Procedure J. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure K. In one embodiment, the compounds provided hereinmay be prepared using General Procedure L. In one embodiment, thecompounds provided herein may be prepared using General Procedure M. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure N. In one embodiment, the compounds provided hereinmay be prepared using General Procedure O. In one embodiment, thecompounds provided herein may be prepared using General Procedure P. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure Q. In one embodiment, the compounds provided hereinmay be prepared using General Procedure R. In one embodiment, thecompounds provided herein may be prepared using General Procedure S. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure T.

In one embodiment, the compounds provided herein may be prepared usingGeneral Procedure U. In one embodiment, the compounds provided hereinmay be prepared using General Procedure V. In one embodiment, thecompounds provided herein may be prepared using General Procedure W. Inone embodiment, the compounds provided herein may be prepared usingGeneral Procedure X. In one embodiment, the compounds provided hereinmay be prepared using General Procedure Y. In one embodiment, thecompounds provided herein may be prepared using General Procedure Z. Inone embodiment, the compounds provided herein may be prepared using anyone or more of General Procedures AA to ZZ. In one embodiment, thecompounds provided herein may be prepared using General Procedure AAA.In one embodiment, the compounds provided herein may be prepared usingGeneral Procedure BBB.

In one embodiment, the compound of formula (I-B) may be preparedfollowing Schemes 9-11, using suitable starting materials known in theart and/or available from a commercial source. In one embodiment, thestarting materials of Schemes 9-11 may be prepared from commerciallyavailable compounds using procedures and conditions known in the art.Exemplary procedures and conditions are provided herein elsewhere.

In one embodiment, a suitable triphenylphosphine halide (e.g.,methyltriphenyl-phosphine chloride) is reacted with a suitable aldehydein the presence of a base to render a substituted alkene, which may befurther reduced (e.g., by hydrogenation) to render a substituted alkanecompound as shown in Scheme 9. In one embodiment, D or E may be furtherconverted to other suitable embodiments of D or E (e.g., transformationof substitution groups) using procedures and conditions known in theart.

Conditions and starting materials other than the Wittig reaction may beemployed in the preparation of a compound of formula (I-B). For example,in one embodiment, a suitable D-CH₃ may be reacted with a suitablealdehyde in the presence of acid (e.g., acetic acid, zinc chloride,heating) to render a substituted alkene, which may be further reduced(e.g., by hydrogenation) to render a substituted alkane compound asshown in Scheme 10. In one embodiment, D or E may be further convertedto other suitable embodiments of D or E (e.g., transformation ofsubstitution groups) using procedures and conditions known in the art.

In another embodiment, a suitable D-CH₃ is reacted with a suitablealdehyde in the presence of acid (e.g., acetic acid, heating) to rendera substituted hydroxylethylene compound (Scheme 11), which is convertedto the corresponding chloride (e.g., using SOCl₂) and reduced (e.g.,using Pd on Carbon) to render a substituted alkane compound as shown inScheme 11. In one embodiment, D or E may be further converted to othersuitable embodiments of D or E (e.g., transformation of substitutiongroups) using procedures and conditions known in the art.

In certain embodiments, the compounds provided herein are prepared as amixture of two or more stereoisomers or diastereoisomers. In oneembodiment, the stereoisomers or diastereoisomers are separated usingtechniques known to those skilled in the art, including but not limitedto, chiral column chromatography and chiral resolution by forming a saltwith a suitable chiral counterion. In certain embodiments, the compoundsprovided herein are prepared following one or more stereoselectivereaction(s). In some embodiment, the compounds provided herein areprepared as a substantially pure stereoisomer.

D. Methods of Use 1. Modulation of PDE Enzyme Activity

In one embodiment, provided herein is a method of binding a compoundprovided herein to a PDE enzyme, such as, PDE-10, in one embodiment,PDE-10A. The method comprises contacting the PDE enzyme with a compoundprovided herein. In one embodiment, the binding to PDE enzyme isassessed using an in vitro binding assay, such as those known in theart.

In one embodiment, provided herein is a method of modulating (e.g.,inhibiting or augmenting) the activity of a PDE enzyme, such as, PDE-10,in one embodiment, PDE-10A. In one embodiment, provided herein is amethod of inhibiting the activity of a PDE enzyme, such as, PDE-10, inone embodiment, PDE-10A. In one embodiment, the method comprisescontacting a PDE enzyme, such as PDE-10A, with a compound providedherein, in vitro or in vivo. In one embodiment, the PDE enzyme, such asPDE-10A, is contacted by a compound provided herein by administering toa subject a therapeutically effective amount of the compound providedherein, or a pharmaceutically acceptable salt or stereoisomer thereof.The subject may be a human. In one embodiment, the PDE enzyme is PDE-10.In one embodiment, the PDE enzyme is PDE-10A.

In other embodiments, the compound provided herein inhibits the activityof a PDE enzyme, such as PDE-10A. Inhibition of PDE activity may bemeasured using assays known in the art. In some embodiments, theactivity of the PDE enzyme is inhibited or reduced by about 1%, about5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%,about 70%, about 80%, about 90%, about 95%, about 99% or more than about99%, as compared with activity without contacting the PDE enzyme with acompound provided herein (e.g., vehicle condition). In one embodiment,the inhibition of enzyme activity is dose dependent. Exemplary assaymethods include, but are not limited to, in vitro binding assays and invitro functional assays. In one embodiment, the functional assayutilizes an appropriate cell-line expressing a desired PDE enzyme, suchas PDE-10A. In one embodiment, the functional assay utilizes a PDEenzyme purified following expression using an appropriate recombinantsystem. In one embodiment, inhibition of PDE enzyme activity may beassessed using a fluorescent assay, e.g., utilizing afluorescently-labeled cAMP/cGMP substrate. In one embodiment, thefunctional assay utilizes synaptosomes isolated from brain tissue of anappropriate organism. In one embodiment, the assay is carried out invivo and involves treatment of a test subject (e.g., a rodent) with acompound provided herein. In one embodiment, a test subject is treatedwith a reference compound or vehicle, as positive or negative controls.In one embodiment, the assay is followed by isolation of brain tissueand ex vivo analysis of substrate concentration (e.g., cAMP or cGMP) inthe brain tissue. In one embodiment, the assay is followed by isolationof brain microdialysates and ex vivo analysis of substrate concentration(e.g., cAMP or cGMP) in the microdialysates.

In certain embodiments, provided herein are methods of inhibiting theactivity of a PDE enzyme, e.g., PDE-10A, in a subject (e.g., human)comprising administering to the subject an effective amount of acompound provided herein. In some embodiments, the activity of PDEenzyme is inhibited by about 1%, about 5%, about 10%, about 20%, about30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%,about 95%, about 99%, or more than about 99%, when measured using anassay described herein elsewhere.

In one embodiment, provided herein is a method of inhibiting a PDEenzyme to increase the concentration of a cyclic nucleotide substrate.In one embodiment, the method includes contacting the cell with acompound provided herein. In one embodiment, the cell is a brain cell,such as a medium spiny neuron. In one embodiment, the enzyme inhibitionoccurs in vitro. In one embodiment, the enzyme inhibition occurs invivo. Thus, in certain embodiments, provided herein are methods ofincreasing the level of a cyclic nucleotide substrate (e.g., cAMP orcGMP) comprising administering to a subject (e.g., human) an effectiveamount of a compound provided herein.

Inhibition of PDE enzyme can be shown, for example, by performingvarious in vitro functional assays utilizing a cell type which expressesa certain type of PDE enzyme, such as PDE-10A, together with anappropriate labeled cyclic nucleotide substrate. In some embodiments,the compounds provided herein inhibit the PDE enzyme in a dose-dependentmanner, with an EC₅₀ of, for example, between about 0.1 nM and about 10μM, between about 1 nM and about 1 μM, between about 1 nM and about 500nM, and between about 1 nM and about 100 nM, in a functional PDEinhibition assay, such as those described herein. In one embodiment, theEC₅₀ is less than about 0.01 nM, less than about 0.1 nM, less than about1 nM, less than about 3 nM, less than about 10 nM, less than about 30nM, less than about 100 nM, less than about 300 nM, less than about 1000nM, less than about 3000 nM, or less than about 10000 nM. In oneembodiment, the EC₅₀ is about 0.01 nM, about 0.1 nM, about 1 nM, about 3nM, about 10 nM, about 30 nM, about 100 nM, about 300 nM, about 1000 nM,about 3000 nM, or about 10000 nM.

2. Treatment, Prevention, and/or Management of Disorders

In one embodiment, provided herein is a method for the treatment,prevention, and/or management of various disorders, including a disorderof the central nervous system, comprising administering a compound or acomposition provided herein. In one embodiment, provided herein is amethod for the treatment, prevention, and/or amelioration of one or moresymptoms of a disorder (e.g., a CNS disorder), comprising administeringa compound or a composition provided herein. In one embodiment, thedisorders provided herein include, but are not limited to,schizophrenia, psychosis, cognitive disorders, mood disorders,depression, attention deficit disorders, and neurodegenerative diseases.In one embodiment, the disorders include, but are not limited to,neurological disorder, schizophrenia, schizophrenia-related disorders,schizophrenia spectrum disorder, acute schizophrenia, chronicschizophrenia, NOS schizophrenia, schizoaffective disorder,schizophreniform disorder, paraphrenia, paranoid personality disorder,schizoid personality disorder, schizotypal personality disorder,delusional disorder, psychosis, disease having a psychosis component,psychotic disorder, brief psychotic disorder, Alzheimer's psychosis,Parkinson's psychosis, shared psychotic disorder, substance-inducedpsychotic disorder (e.g., cocaine, alcohol, amphetamine), psychoticdisorder due to a general medical condition, psychoaffective disorder,aggression, delirium, excitative psychosis, Tourette's syndrome, manicdisorder, organic psychosis, NOS psychosis, convulsion, seizure,agitation, posttraumatic stress disorder, behavior disorder,neurodegenerative disease, Huntington's disease, Alzheimer's disease,Parkinson's disease, dyskinesia, dementia, mood disorder, bipolardisorder, anxiety, depression, major depressive disorder, unipolardepression, treatment resistant depression, dysthymia, affectivedisorder, seasonal affective disorder, obsessive-compulsive disorder,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), vertigo, pain, neuropathic pain, sensitizationaccompanying neuropathic pain, inflammatory pain, fibromyalgia,migraine, cognitive impairment, cognitive impairment associated withschizophrenia, cognitive deficit in Alzheimer's disease, cognitivedeficit in Parkinson's disease, movement disorder, restless leg syndrome(RLS), multiple sclerosis, sleep disorder, substance abuse or dependency(e.g., nicotine, cocaine), addiction, eating disorder, autism, obesity,undesirable weight retention or weight gain, metabolic syndrome,diabetes, non-insulin dependent diabetes, impaired glucose tolerance,and hyperglycemia. In one embodiment, the disorder provided herein is adisorder known in the art that affects the central nervous system (i.e.,a CNS disorder).

In one embodiment, provided herein is a method of administering acompound provided herein in a disease model that is known in the art. Inone embodiment, the disease model is an animal model. In one embodiment,provided herein is a method of administering the compound providedherein in an animal model that is predictive of efficacy in thetreatment of certain diseases in a human. The method comprisesadministering a compound provided herein in a subject. In oneembodiment, the method comprises administering to a subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt or stercoisomer thereof. In oneembodiment, the method comprises treatment of a test subject (e.g., amice or rat) with a compound provided herein. In one embodiment, themethod comprises treatment of a test subject (e.g., a mouse or rat) witha compound provided herein as well as a reference compound. In oneembodiment, the in vivo activity of the compound provided herein is dosedependent. In one embodiment, without being limited to a particulartheory, the method provided herein comprises administering an effectiveamount of a compound provided herein to inhibit PDE-10 activity in asubject. In one embodiment, without being limited to a particulartheory, the method provided herein comprises administering an effectiveamount of a compound provided herein to inhibit PDE-10A activity in asubject.

In one embodiment, the compounds provided herein are active in one ormore animal models of schizophrenia or psychosis, such as conditionedavoidance responding (CAR), auditory gating (e.g., amphetamine-induceddeficit in auditory gating), phencyclidine (PCP)-inducedhyperlocomotion, stimulant-induced hyperlocomotion/hyperactivity,PCP-induced hyperactivity, and amphetamine-induced hyperactivity. In oneembodiment, the compounds provided herein inhibit exploratory locomotoractivity and/or hyperactivity caused by a dopamine releasing agent, suchas amphetamine, and/or a NMDA receptor antagonist, such as phencyclidine(PCP). In one embodiment, the compounds provided herein inhibitconditioned avoidance responding. In one embodiment, the compoundsprovided herein are active in pre-pulse inhibition (PPI) of acousticstartle response model. In one embodiment, the compounds provided hereininhibit spontaneous locomotor activity. In one embodiment, the compoundsprovided herein improve cognitive function in a treated subject. In oneembodiment, the compounds provided herein improve social interaction ina treated subject. In one embodiment, the compounds provided hereinimprove social cognition in a treated subject. In one embodiment, thecompounds provided herein improve executive function in a treatedsubject. In one embodiment, the compounds provided herein caused reducedParkinsonian side effects in a treated subject. In one embodiment, thecompounds provided herein produce relatively low levels of catalepsy, ascompared to other therapeutic agents. In one embodiment, the compoundsprovided herein provide a neuron-protective effect on neurons, such asmedium spiny neurons, in a treated subject. In one embodiment, thecompounds provided herein are active in a striatal quinolinic acidlesion model for Huntington's disease. In one embodiment, the compoundsprovided herein are active in dizocilpine-induced hyperactivity andstereotyped sniffing model for psychosis. In one embodiment, thecompounds provided herein inhibit apomorphine-induced climbing. In oneembodiment, the compounds provided herein inhibit N-methyl-D-aspartateantagonist-induced deficits in pre-pulse inhibition of acoustic startleresponse. In one embodiment, the compounds provided herein improvebaseline sensory gating. In one embodiment, the compounds providedherein increase sociality in a social approach/social avoidance assay.In one embodiment, the compounds provided herein enhance social odorrecognition. In one embodiment, the compounds provided herein improvenovel object recognition. In one embodiment, the compounds providedherein are active in a disease model for a disorder provided hereinelsewhere, which is known in the art. See, e.g., Grauer et al.,Phosphodiesterase 10A Inhibitor Activity in Preclinical Models of thePositive, Cognitive, and Negative Symptoms of Schizophrenia, Journal ofPharmacology and Experimental Therapeutics, 2009, 331(2), 574-90;Threlfell et al., Inhibition of Phosphodiesterase 1 OA Increases theResponsiveness of Striatal Projection Neurons to Cortical Stimulation,Journal of Pharmacology and Experimental Therapeutics, 2009, 328(3),785-95; Schmidt et al., Preclinical Characterization of SelectivePhosphodiesterase 10A Inhibitors: A New Therapeutic Approach to theTreatment of Schizophrenia, Journal of Pharmacology and ExperimentalTherapeutics, 2008, 325(2), 681-90.

In one embodiment, provided herein is a method of treating, preventing,and/or managing various disorders, including, but not limited to, adisorder of the central nervous system. In one embodiment, the methodcomprises administering to a subject (e.g., human) a therapeutically orprophylactically effective amount of a composition or a compoundprovided herein. In one embodiment, the subject is a human. In oneembodiment, the subject is an animal. In one embodiment, the compoundsprovided herein are highly brain penetrable in the subject. In certainembodiments, the efficacious concentration of the compounds providedherein is less than 10 nM, less than 100 nM, less than 1 μM, less than10 μM, less than 100 μM, or less than 1 mM. In one embodiment, thecompound's activity may be assessed in various art-recognized animalmodels as described herein elsewhere or known in the literature.

In one embodiment, without being limited by a particular theory, thetreatment, prevention, and/or management is done by administering acompound provided herein that has shown in vivo efficacy in an animalmodel predictive of efficacy in humans.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disorder related to a CNS disorder, a neurologicaldisorder, schizophrenia, a schizophrenia-related disorder, schizophreniaspectrum disorder, acute schizophrenia, chronic schizophrenia, NOSschizophrenia, schizoaffective disorder, schizophreniform disorder,paraphrenia, paranoid personality disorder, schizoid personalitydisorder, schizotypal personality disorder, delusional disorder,psychosis, a disease having a psychosis component, psychotic disorder,brief psychotic disorder, Alzheimer's psychosis, Parkinson's psychosis,shared psychotic disorder, substance-induced psychotic disorder (e.g.,cocaine, alcohol, amphetamine), psychotic disorder due to a generalmedical condition, psychoaffective disorder, aggression, delirium,excitative psychosis, ‘Tourette’s syndrome, manic disorder, organicpsychosis, NOS psychosis, convulsion, seizure, agitation, posttraumaticstress disorder, behavior disorder, neurodegenerative disease,Huntington's disease, Alzheimer's disease, Parkinson's disease,dyskinesias, dementia, mood disorder, bipolar disorder, anxiety,depression, major depressive disorder, unipolar depression, treatmentresistant depression, dysthymia, affective disorder, seasonal affectivedisorder, obsessive-compulsive disorder, attention deficit disorder(ADD), attention deficit hyperactivity disorder (ADHD), vertigo, pain,neuropathic pain, sensitization accompanying neuropathic pain,inflammatory pain, fibromyalgia, migraine, cognitive impairment,cognitive impairment associated with schizophrenia, cognitive deficit inAlzheimer's disease, cognitive deficit in Parkinson's disease, movementdisorder, restless leg syndrome (RLS), multiple sclerosis, sleepdisorder, substance abuse or dependency (e.g., nicotine, cocaine),addiction, eating disorder, autism, obesity, undesirable weightretention or weight gain, metabolic syndrome, diabetes, non-insulindependent diabetes, impaired glucose tolerance, or hyperglycemia,comprising administering to a subject an effective amount of a compoundprovided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurological disorder as provided herein elsewhere,such as schizophrenia, psychosis, cognitive impairment, depression,Alzheimer's disease, Parkinson's disease, and attention deficithyperactivity disorder (ADHD), and the like, comprising administering toa subject an effective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing schizophrenia or a schizophrenia-related disorder,including but not limited to schizophrenia spectrum disorder, acuteschizophrenia, chronic schizophrenia, NOS schizophrenia, schizoaffectivedisorder, schizophreniform disorder, paraphrenia, paranoid personalitydisorder, schizoid personality disorder, schizotypal personalitydisorder, delusional disorder, and psychosis, comprising administeringto a subject an effective amount of a compound provided herein. In oneembodiment, the compounds provided herein treat, prevent, and/orameliorate one or more positive symptoms of schizophrenia. In oneembodiment, the compounds provided herein treat, prevent, and/orameliorate one or more negative symptoms of schizophrenia. In oneembodiment, the compounds provided herein treat, prevent, and/orameliorate one or more cognitive symptoms of schizophrenia.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disease having a psychosis component, including butnot limited to psychotic disorder, brief psychotic disorder, Alzheimer'spsychosis, Parkinson's psychosis, shared psychotic disorder,substance-induced psychotic disorder (e.g., cocaine, alcohol, oramphetamine), psychotic disorder due to a general medical condition,psychoaffective disorder, aggression, delirium, excitative psychosis,‘lourette’s syndrome, manic disorder, organic psychosis, and NOSpsychosis, comprising administering to a subject an effective amount ofa compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing cognitive impairment, including but not limited tocognitive impairment associated with schizophrenia, cognitive deficit inAlzheimer's disease, cognitive deficit in Parkinson's disease,comprising administering to a subject an effective amount of a compoundprovided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing mood disorder, bipolar disorder, anxiety, depression,major depressive disorder, unipolar depression, treatment resistantdepression, dysthymia, affective disorder, seasonal affective disorder,or obsessive-compulsive disorder, comprising administering to a subjectan effective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing attention deficit disorder (ADD) or attention deficithyperactivity disorder (ADHD), comprising administering to a subject aneffective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurodegenerative disease, including but not limitedto IIuntington's disease, Alzheimer's disease, and Parkinson's disease,comprising administering to a subject an effective amount of a compoundprovided herein. In one embodiment, provided herein is a method oftreating, preventing, and/or managing Huntington's disease, comprisingadministering to a subject an effective amount of a compound providedherein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing agitation, posttraumatic stress disorder, or behaviordisorder, comprising administering to a subject an effective amount of acompound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing dementia, comprising administering to a subject aneffective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing vertigo, comprising administering to a subject aneffective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing pain, neuropathic pain, sensitization accompanyingneuropathic pain, inflammatory pain, migraine or fibromyalgia,comprising administering to a subject an effective amount of a compoundprovided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing movement disorder or restless leg syndrome (RLS),comprising administering to a subject an effective amount of a compoundprovided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing multiple sclerosis, sleep disorder, substance abuse ordependency (e.g., nicotine, cocaine), addiction, eating disorder, orautism, comprising administering to a subject an effective amount of acompound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disorder related to cognitive impairments, such asthose associated with Alzheimer s disease, Parkinson's disease,schizophrenia, and attention deficit hyperactivity disorder (ADHD), andthe like, comprising administering to a subject an effective amount of acompound provided herein. For example, without being limited by aparticular theory, the compounds provided herein may have pro-cognitiveeffects, such as passive avoidance, novel object recognition, socialrecognition, and attention-set shifting. Further, without being limitedby a particular theory, the compounds provided herein may improve socialmemory, increase the acquisition of an environment, and reversescopolamine-induced deficits. The compounds provided herein may alsoreverse scopolamine-induced deficits in a passive avoidance memory test.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a psychotic disorder or psychotic condition, includingbut not limited to, schizophrenia, delusional disorders and drug inducedpsychosis, comprising administering to a subject an effective amount ofa compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing an anxiety disorder, including but not limited to, panicand obsessive-compulsive disorder, comprising administering to a subjectan effective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a movement disorder, including but not limited to,Parkinson's disease and Huntington's disease, comprising administeringto a subject an effective amount of a compound provided herein.

In one embodiment, the psychotic disorders provided herein that can betreated, prevented, and/or managed using a compound or a pharmaceuticalcomposition provided herein include, but are not limited to,schizophrenia, e.g., of the paranoid, disorganized, catatonic,undifferentiated, and/or residual type; schizophreniform disorder;schizoaffective disorder, e.g., of the delusional and/or depressivetype; delusional disorder; substance-induced psychotic disorder, e.g.,psychosis induced by alcohol, amphetamine, cannabis, cocaine,hallucinogens, inhalants, opioids, and/or phencyclidine; personalitydisorder of the paranoid type; and personality disorder of the schizoidtype.

In one embodiment, the movement disorders provided herein that can betreated, prevented, and/or managed using a compound or a pharmaceuticalcomposition provided herein include, but are not limited to,Huntington's disease, dyskinesia associated with dopamine agonisttherapy, Parkinson's disease, restless leg syndrome, and essentialtremor.

In one embodiment, other disorders provided herein that can be treated,prevented, and/or managed using a compound or a pharmaceuticalcomposition provided herein include, but are not limited to,obsessive-compulsive disorder, Tourette's syndrome, and tic disorders.

In one embodiment, provided herein is a method of treating, preventing,and/or managing an anxiety disorder, including but not limited to, panicdisorder, agoraphobia, specific phobia, social phobia,obsessive-compulsive disorder, post-traumatic stress disorder, acutestress disorder, and generalized anxiety disorder, comprisingadministering to a subject an effective amount of a compound providedherein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a drug addiction, including but not limited to, analcohol, amphetamine, cocaine, and/or opiate addiction, comprisingadministering to a subject an effective amount of a compound providedherein. In one embodiment, the drug addiction provided herein representsan abnormal desire for a drug and is generally characterized bymotivational disturbances such a compulsion to take the desired drug andepisodes of intense drug craving.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disorder comprising a symptom of deficiency inattention and/or cognition, comprising administering to a subject aneffective amount of a compound provided herein. In one embodiment,deficiency in attention and/or cognition provided herein may represent asubnormal functioning in one or more cognitive aspects, such as, e.g.,memory, intellect, learning ability, and/or logic ability, in aparticular subject relative to other subjects within the same generalpopulation and/or age group. In one embodiment, deficiency in attentionand/or cognition provided herein may represent a reduction in aparticular sub-population's functioning in one or more cognitiveaspects, such as, e.g., in age-related cognitive decline.

In one embodiment, the disorders comprising a symptom of deficiency inattention and/or cognition provided herein that can be treated,prevented, and/or managed with a compound or a pharmaceuticalcomposition provided herein, include, but are not limited to, dementia,e.g., dementia in Alzheimer's disease, multi-infarct dementia, alcoholicdementia, drug-related dementia, dementia associated with intracranialtumors, dementia associated with cerebral trauma, dementia associatedwith Huntington's disease, dementia associated with Parkinson's disease,or AIDS-related dementia; delirium; amnestic disorder; post-traumaticstress disorder; mental retardation; learning disorder, e.g., readingdisorder, mathematics disorder, or a disorder of written expression;attention-deficit/hyperactivity disorder; and age-related cognitivedecline.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a mood disorder or a mood episode, comprisingadministering to a subject an effective amount of a compound providedherein. In one embodiment, the mood disorders or mood episodes providedherein that can be treated, prevented, and/or managed with a compound ora pharmaceutical composition provided herein include, but are notlimited to, major depressive episode of the mild, moderate or severetype; a manic or mixed mood episode; a hypomanic mood episode; adepressive episode with atypical features; a depressive episode withmelancholic features; a depressive episode with catatonic features; amood episode with postpartum onset; post-stroke depression; majordepressive disorder; treatment resistant depression; dysthymic disorder;minor depressive disorder; premenstrual dysphoric disorder;post-psychotic depressive disorder of schizophrenia; a major depressivedisorder superimposed on a psychotic disorder such as delusionaldisorder or schizophrenia; a bipolar disorder, e.g., bipolar I disorder,bipolar II disorder, and cyclothymic disorder.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurodegenerative disorder or neurodegenerativecondition, comprising administering to a subject an effective amount ofa compound provided herein. In one embodiment, the neurodegenerativedisorder or neurodegenerative condition provided herein that can betreated, prevented, and/or managed with a compound or a pharmaceuticalcomposition provided herein represents a disorder or condition that iscaused by the dysfunction and/or death of neurons in the central nervoussystem. The treatment of these disorders and conditions can befacilitated by administration of an agent which prevents the dysfunctionor death of neurons at risk and/or enhances the function of damaged orhealthy neurons to compensate for the loss of function caused by thedysfunction or death of at-risk neurons. In one embodiment, theneurodegenerative disorders or neurodegenerative conditions providedherein that can be treated, prevented, and/or managed with a compound ora pharmaceutical composition provided herein include, but are notlimited to, Parkinson's disease; Huntington's disease; dementia, e.g.,Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, andFronto temperal dementia; neurodegeneration associated with cerebraltrauma; neurodegeneration associated with stroke; neurodegenerationassociated with cerebral infarct; hypoglycemia-inducedneurodegeneration; neurodegeneration associated with neurotoxinpoisoning; and multi-system atrophy. In one embodiment, theneurodegenerative disorders or neurodegenerative conditions providedherein comprise neurodegeneration of striatal medium spiny neurons in asubject. In one embodiment, the neurodegenerative disorder orneurodegenerative condition is Huntington's disease.

In one embodiment, provided herein is a method of treating, preventing,and/or managing psychotic disorder, delusional disorder, drug inducedpsychosis, anxiety disorder, movement disorder, mood disorder,neurodegenerative disorder, or drug addiction, comprising administeringto a subject an effective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurologic disorder, including but not limited to,dementia, Alzheimer's disease, multi-infarct dementia, alcoholicdementia, drug-related dementia, dementia associated with intracranialtumors, dementia associated with cerebral trauma, dementia associatedwith Huntington's disease, dementia associated with Parkinson's disease,AIDS-related dementia, delirium, anmestic disorder, post-traumaticstress disorder, mental retardation, learning disorder, readingdisorder, mathematics disorder, disorder of written expression,attention-deficit-hyperactivity disorder, age-related cognitive decline,major depressive episode of the mild, moderate or severe type, manic ormixed mood episode, hypomanic mood episode, depressive episode withatypical features, depressive episode with melancholic features,depressive episode with catatonic features, mood episode with postpartumonset, post-stroke depression, major depressive disorder, dysthymicdisorder, minor depressive disorder, premenstrual dysphoric disorder,post-psychotic depressive disorder of schizophrenia, a major depressivedisorder superimposed on a psychotic disorder comprising a delusionaldisorder or schizophrenia, bipolar disorder, bipolar I disorder, bipolarII disorder, cyclothymic disorder, Parkinson's disease, Huntington'sdisease, dementia, Alzheimer's disease, multi-infarct dementia,AIDS-related dementia, Fronto temperal dementia, neurodegenerationassociated with cerebral trauma, neurodegeneration associated withstroke, neurodegeneration associated with cerebral infarct,hypoglycemia-induced neurodegeneration, neurodegeneration associatedwith neurotoxin poisoning, multi-system atrophy, schizophrenia of aparanoid, disorganized, catatonic, undifferentiated or residual type,schizophreniform disorder; schizoaffective disorder of the delusionaltype or the depressive type, delusional disorder, substance-inducedpsychotic disorder, psychosis induced by alcohol, amphetamine, cannabis,cocaine, hallucinogens, inhalants, opioids, or phencyclidine,personality disorder of the paranoid type, and personality disorder ofthe schizoid type, comprising administering to a subject an effectiveamount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurologic disorder, including but not limited to,psychotic disorders, delusional disorders, drug induced psychosis,anxiety disorders, movement disorders, mood disorders, neurodegenerativedisorders, and drug addiction, comprising administering to a subject aneffective amount of a compound provided herein.

In one embodiment, provided herein is a method of treating, preventing,and/or managing substance abuse, comprising administering to a subjectan effective amount of a compound provided herein. For example, withoutbeing limited by a particular theory, the compounds provided herein mayalter methamphetamine self-administration in rats, and therefore thecompounds provided herein may ameliorate the craving for addictivedrugs.

In one embodiment, provided herein is a method of using the compoundsprovided herein as psycho-stimulants, which may lack the abuseliabilities generally associated with other classes ofpsycho-stimulants.

In one embodiment, provided herein is a method of treating, preventing,and/or managing movement disorders, such as Parkinson's disease, L-dopainduced dyskineasias, peak dose dyskinesas, restless leg syndrome (RLS),and Huntington's disease, comprising administering to a subject aneffective amount of a compound provided herein.

In some embodiments, the compounds provided herein are active in atleast one model, which can be used to measure the activity of thecompounds and estimate their efficacy in treating a CNS disorder. Forexample, the compounds provided herein are active in at least one modelfor schizophrenia, such as, e.g., conditioned avoidance responding,amphetamine-induced deficit in auditory gating, phencyclidine-inducedhyperlocomotion or hyperactivity, and amphetamine-induced hyperactivitymodels. The compounds are active when they induce a desired response inthe animal (e.g., mice) by a statistically significant amount comparedto vehicle-treated animals.

In other embodiments, provided herein is a method of effecting atherapeutic effect as described herein elsewhere. The method comprisesadministering to a subject (e.g., a mammal) a therapeutically effectiveamount of a compound or a composition provided herein.

The particular therapeutic effects may be measured using any modelsystem known in the art and described herein, such as those involving ananimal model of a disease.

In some embodiments, the neurological disorder provided herein is:depression (e.g., major depressive disorder, bipolar disorder, unipolardisorder, treatment resistant depression, dysthymia, and seasonalaffective disorder); cognitive deficits; fibromyalgia; pain (e.g.,neuropathic pain); sleep related disorders (e.g., sleep apnea, insomnia,narcolepsy, cataplexy) including those sleep disorders which areproduced by psychiatric conditions; chronic fatigue syndrome; attentiondeficit disorder (ADD); attention deficit hyperactivity disorder (ADHD);restless leg syndrome; schizophrenia; anxieties (e.g., general anxietydisorder, social anxiety disorder, panic disorder); obsessive compulsivedisorder; posttraumatic stress disorder; seasonal affective disorder(SAD); premenstrual dysphoria; post-menopausal vasomotor symptoms (e.g.,hot flashes, night sweats); neurodegenerative disease (e.g., Parkinson'sdisease, Alzheimer's disease and amyotrophic lateral sclerosis); manicconditions; dysthymic disorder; cyclothymic disorder; obesity; andsubstance abuse or dependency (e.g., cocaine addiction, nicotineaddiction). In another embodiment, the compounds provided herein areuseful to treat, prevent, and/or manage two or moreconditions/disorders, which are co-morbid, such as psychosis anddepression.

Neurological disorders may also include cerebral function disorders,including without limitation, senile dementia, Alzheimer's typedementia, cognition, memory loss, amnesia/amnestic syndrome, lowering ofattention, speech disorders, autism, and hyperkinctic syndrome.

Neuropathic pain includes, without limitation, post herpetic (orpost-shingles) neuralgia, reflex sympathetic dystrophy/causalgia ornerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

Other exemplary diseases and conditions that may be treated, prevented,and/or managed using the methods, compounds, and/or compositionsprovided herein include, but are not limited to: obesity, overweight,metabolic syndrome, diabetes, non-insulin dependent diabetes, impairedglucose tolerance, and hyperglycemia.

In one embodiment, the neurological disorder is excessive daytimesleepiness. In another embodiment, the neurological disorder iscognitive impairment. In another embodiment, the neurological disorderis mood disorders. In another embodiment, the neurological disorder ismovement disorders. In another embodiment, the neurological disorder isschizophrenia. In another embodiment, the neurological disorder isattention disorders. In another embodiment, the neurological disorder isanxiety disorder. In another embodiment, the neurological disorder isseizure. In another embodiment, the neurological disorder is psychosis.In another embodiment, the neurological disorder is vertigo. In anotherembodiment, the neurological disorder is pain. In another embodiment,the neurological disorder is neuropathic pain. In another embodiment,the neuropathic pain is diabetic neuropathy.

In one embodiment, the neurological disorder is a neurodegenerativedisease. In one embodiment, the neurodegenerative disease is Parkinson'sdisease. In another embodiment, the neurodegenerative disorder isAlzheimer's disease.

In one embodiment, the compounds described herein treat, prevent, and/ormanage a central nervous disorder, without causing addiction to saidcompounds.

Any suitable route of administration can be employed for providing thepatient with a therapeutically or prophylactically effective dose of anactive ingredient. For example, oral, mucosal (e.g., nasal, sublingual,buccal, rectal, vaginal), parenteral (e.g., intravenous, intramuscular),transdermal, and subcutaneous routes can be employed. Exemplary routesof administration include oral, transdermal, and mucosal. Suitabledosage forms for such routes include, but are not limited to,transdermal patches, ophthalmic solutions, sprays, and aerosols.

Transdermal compositions can also take the form of creams, lotions,and/or emulsions, which can be included in an appropriate adhesive forapplication to the skin or can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose. An exemplary transdermal dosage form is a “reservoir type” or“matrix type” patch, which is applied to the skin and worn for aspecific period of time to permit the penetration of a desired amount ofactive ingredient. The patch can be replaced with a fresh patch whennecessary to provide constant administration of the active ingredient tothe patient.

The amount to be administered to a patient to treat, prevent, and/ormanage the disorders described herein will depend upon a variety offactors including the activity of the particular compound employed, orthe ester, salt or amide thereof, the route of administration, the timeof administration, the rate of excretion or metabolism of the particularcompound being employed, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount required. For example, thephysician or veterinarian could start doses of the compounds employed atlevels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound provided herein will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic or prophylactic effect. Such an effective dosewill generally depend upon the factors described above. The dosage maybe formulated as a single or multiple unit dosage formulation. In oneembodiment, the compound is given in single or divided doses per day.

In some embodiments, the compounds disclosed herein may be used incombination with one or more second active agents to treat, prevent,and/or manage disorders described herein.

In certain embodiments, the second active agent is an antipsychoticagent. In certain embodiments, the second active agent is an atypicalantipsychotic agent. In certain embodiments, the second active agent isan agent that is useful for the treatment of Alzheimer's disease. Incertain embodiments, the second active agent is a cholinesteraseinhibitor. In certain embodiments, the second active agent is anantidepressant, including, but not limited to, an SNRI, SSRI, TCA, or anMAOI.

In certain embodiments, the second active agent is lurasidone,olanzapine, risperidone, aripiprazole, amisulpride, asenapine,blonanserin, clozapine, clotiapine, illoperidone, mosapramine,paliperidone, quetiapine, remoxipride, sertindole, sulpiride,ziprasidonc, zotcpine, pimavanscrin, loxapine, donepezil, rivastigmine,memantine, galantamine, tacrine, amphetamine, methylphenidate,atomoxetine, modafinil, sertraline, fluoxetine, duloxetine, venlafaxine,phenelzine, selegiline, imipramine, desipramine, clomipramine, orL-DOPA.

3. Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, stereoisomer, solvate, clathrate, orprodrug thereof. Pharmaceutical compositions and dosage forms canfurther comprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are also disclosed herein.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintra-arterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another and will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, 18th Ed., MackPublishing, Easton Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or disaccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising, active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipicnts, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients.

In other embodiments, dosage forms comprise the second activeingredient. The specific amount of the second active agent will dependon the specific agent used, the diseases or disorders being treated ormanaged, and the amount(s) of a compound provided herein, and anyoptional additional active agents concurrently administered to thepatient.

(a) Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington's TheScience and Practice of Pharmacy, 21st Ed., Lippincott Williams &Wilkins (2005).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or non-aqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Aspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, and optional excipients, such as anhydrous lactose,microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin.

(b) Controlled Release Dosage Forms

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. In one embodiment, provided aresingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

In one embodiment, controlled-release pharmaceutical products improvedrug therapy over that achieved by their non-controlled counterparts. Inanother embodiment, the use of a controlled-release preparation inmedical treatment is characterized by a minimum of drug substance beingemployed to cure or control the condition in a minimum amount of time.

Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

In another embodiment, the controlled-release formulations are designedto initially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In one embodiment, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

(c) Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intra-arterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient.

Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection,suspensions ready for injection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodcxtrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

(d) Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipicnts (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

4. Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise one or more second active ingredientsas described herein, or a pharmacologically active mutant or derivativethereof, or a combination thereof.

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

V. EXAMPLES

Certain embodiments are illustrated by the following non-limitingexamples.

A. General Procedures for Compound Synthesis

In the examples below, unless otherwise indicated, all temperatures areset forth in degrees Celsius and all parts and percentages are byweight. Reagents may be purchased from commercial suppliers, such asSigma-Aldrich® Chemical Company, and may be used without furtherpurification unless otherwise indicated. Reagents may also be preparedfollowing standard literature procedures known to those skilled in theart. Solvents may be purchased from Aldrich in Sure-Seal® bottles andused as received. All solvents may be purified using standard methodsknown to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally at ambienttemperature, unless otherwise indicated. The reaction flasks were fittedwith rubber septa for introduction of substrates and reagents viasyringe. Analytical thin layer chromatography (TLC) was performed usingglass-backed silica gel pre-coated plates and eluted with appropriatesolvent ratios (v/v). Reactions were assayed by TLC or liquidchromatography mass spectroscopy (LCMS), and terminated as judged by theconsumption of starting material. Visualization of the TLC plates wasdone with UV light (254 wavelength) or with an appropriate TLCvisualizing solvent, such as basic aqueous KMnO₄ solution activated withheat. Flash column chromatography (see, e.g., Still et al., J. Org.Chem., 43: 2923 (1978)) was performed using silica gel 60 or variousmedium-pressure liquid chromatography (MPLC) systems (such as Biotage®or ISCO® separation systems).

The compound structures in the examples below were confirmed by one ormore of the following methods: proton magnetic resonance spectroscopy,mass spectroscopy, elemental microanalysis, and melting point. Protonnuclear magnetic resonance (¹H NMR) spectra were determined using a NMRspectrometer operating at a certain field strength. Chemical shifts arereported in parts per million (ppm, 6) downfield from an internalstandard, such as tetramethylsilane (TMS). Alternatively, ¹H NMR spectrawere referenced to signals from residual protons in deuterated solventsas follows: CDCl₃=7.25 ppm; DMSO-d₆=2.49 ppm; C₆D₆=7.16 ppm; CD₃OD=3.30ppm. Peak multiplicities are designated as follows: s, singlet; d,doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets;q, quartet; br, broadened; and m, multiplet. Coupling constants aregiven in Hertz (Hz). Mass spectra (MS) data were obtained using a massspectrometer with APCI or ESI ionization.

In one embodiment, in the schemes below, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶,R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶¹, and R⁶² are each independently a suitablesubstituent; HetAr is heteroaryl; and Ar, Ar¹, and Ar² are eachindependently aryl or heteroaryl. In the scheme for General Procedure A,A and B are each independently N or CR⁶¹. In one embodiment, R^(6′) isH. In the scheme for General Procedure L, X¹ and X² are eachindependently N or CR⁶². In one embodiment, R⁶² is H.

1. General Procedure A

(a) N,N-Dimethyl-4-phenyl-1H-imidazole-1-sulfonamide

To a solution of 5-phenyl-1H-imidazole (5 g, 34.7 mmol) and K₂CO₃ (6 g,41.6 mmol) in N,N-dimethylformamide (DMF) (20 mL) was addeddimethylsulfamoyl chloride (4.11 mL, 38.2 mmol) drop wise at roomtemperature. The resulting mixture was stirred at room temperature for 4h and then diluted with water (500 mL). The resulting solid wascollected by vacuum filtration and dried to give the desired product (7g). LC-MS: m/z 252 (M+H⁺).

(b) 2-Formyl-N,N-di methyl-4-phenyl-1H-imidazole-1-sulfonamide

To a solution of diisopropylamine (12 mL, 85.3 mmol) in tetrahydrofuran(THF) (50 mL) was added n-butyllithium (n-BuLi) (34 mL, 85.3 mmol)dropwise at 0° C. The reaction mixture was stirred for 0.5 h to form asolution of lithium diisopropylamide (LDA). A solution ofN,N-dimethyl-5-phenyl-1H-imidazole-1-sulfonamide (10.7 g, 42.6 mmol) inanhydrous THF (40 mL) was prepared and cooled to −78° C. To thissolution was added dropwise at −78° C. the LDA solution, and thereaction mixture was stirred at −78° C. for additional 0.5 h. AnhydrousDMF (9.9 mL, 128 mmol) was then added rapidly and the mixture wasstirred at −60° C. to −30° C. for 2 h. While the mixture was vigorouslystirred, 10% IIC1 was added dropwise until pII 5. The aqueous layer wasextracted with EtOAc (200 mL×3). The combined organic layers were driedover Na₂SO₄, filtered, and concentrated to give the desired product as asolid (12.5 g). LC-MS: m/z 280 (M+H⁺).

(c) (E,Z)-2-(2-(5-Phenyl-1H-imidazol-2-yl)vinyl)quinoxaline

A mixture of 2-formyl-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide(500 mg, 1.79 mmol), 2-methylquinoxaline (258 mg, 1.79 mmol), and acatalytic amount of ZnCl₂ in glacial acetic acid (10 mL) was stirred at110° C. for 18 h. The reaction mixture was cooled to room temperature,pH was adjusted to 8 with Na₂CO₃, and extracted with EtOAc (50 mL×3).The organic layer was dried over Na₂SO₄, filtered, and concentrated. Theresulting crude product was purified by column chromatography to give 90mg of the desired product. LC-MS: m/z 299 (M+H⁺).

(d) 2-(2-(5-Phenyl-1H-imidazol-2-yl)ethyl)quinoxaline

(E,Z)-2-(2-(5-Phenyl-1H-imidazol-2-yl)vinyl)quinoxaline (90 mg) wasdissolved in MeOH (5 mL). To the mixture was added a catalytic amount ofPd on carbon. A vacuum was applied and the reaction vessel containingthe reaction mixture was back filled with hydrogen gas, three times.After the completion of the reaction, the mixture was filtered and thesolid was rinsed with methanol. The filtrate was concentrated andpurified by column chromatography to give the desired product (21.6 mg).LC-MS: m/z 301 (M+H⁺).

2. General Procedure B

(a) 1,2-Bis(1-methyl-1H-benzo[d]imidazol-2-yl)ethane-1,2-diol

N-Methylbenzene-1,2-diamine (13.5 g, 85.4 mmol) and tartaric acid (6.4g, 42.6 mmol) were dissolved in 4 N aqueous HCl (100 mL), and thesolution was stirred at reflux overnight. After cooling to roomtemperature, the precipitate was collected by vacuum filtration andre-dissolved in water (200 mL), and the pIT of the resulting mixture wasadjusted to 8 with aqueous NH₄OH solution. The precipitate was collectedby vacuum filtration and dried to give 6.86 g of the desired product,which was used for the next step without further purification. LC-MS:m/z 323 (M+H⁺).

(b) 1-Methyl-1H-benzo[d]imidazole-2-carbaldehyde

To a solution of1,2-bis(1-methyl-1H-benzo[d]imidazol-2-yl)ethane-1,2-diol (4.9 g, 15.2mmol) and NaIO₄ (3.3 g, 15.2 mmol) in water (150 mL) was added 3 Naqueous H₂SO₄ (18 mL) dropwise. After stirring at ambient temperatureovernight, the mixture was adjusted to pH 8 with aqueous Na₂CO₃. Theprecipitate was collected by vacuum filtration and washed with water andethanol. The solid was dried to give 3.11 g of the desired product.LC-MS: m/z 161 (M+H⁺).

(c)2-((E,Z)-2-(1-Methyl-1H-benzo[d]imidazol-2-yl)vinyl)quinazolin-4(3H)-one

The title compound was prepared from1-methyl-1H-benzo[d]imidazol-2-carbaldehyde and2-methylquinazolin-4(3H)-one according to General Procedure A-(c).LC-MS: m/z 303 (M+H⁺).

(d) 2-(2-(1-Methyl-1H-benzo[d]imidazol-2-yl)ethyl)quinazolin-4(3H)-one

The title compound was prepared from2-((E,Z)-2-(1-methyl-1H-benzo[d]imidazol-2-yl)vinyl)quinazolin-4(3H)-oneaccording to General Procedure A-(d). LC-MS: m/z 305.1 (M+H⁺).

3. General Procedure C

(a) 2-(3-Chloropropanamido)benzamide

To a solution of 2-aminobenzamide (500 mg, 3.68 mmol) and triethylamine(NEt₃) (450 mg, 4.41 mmol) in CH₃CN (30 mL) was added 3-chloropropanoylchloride (0.45 mL, 4.41 mmol) dropwise at room temperature. Afterstirring overnight, the reaction mixture was concentrated to give thedesired product (800 mg) as solid, which was used for the next stepwithout further purification. LC-MS: m/z 227 (M+H⁺).

(b) 2-(2-(4-Phenyl-1H-imidazol-1-yl)ethyl)quinazolin-4(3H)-one

A solution of 4-phenyl-1H-imidazole (500 mg, 3.47 mmol),2-(3-chloropropanamido)benzamide (1.17 g, 5.21 mmol) and K₂CO₃ (717 mg,5.20 mmol) in DMF (50 mL) was stirred at 110° C. overnight. Aftercooling to room temperature, the reaction mixture was diluted with water(200 ml) and extracted with EtOAc (100 mL×3). The organic layer wasdried over Na₂SO₄, filtered and concentrated. The resulting product waswashed with EtOAc and filtered to give the desired product (60 mg).LC-MS: m/z 317 (M+H⁺).

4. General Procedure D

(a) 3-(Bromomethyl)isoquinolin-1(2H)-one

To a refluxing solution of 3-methylisoquinolin-1(2H)-one (1.7 g, 10.69mmol) and 2-(4-biphenyl)-5-phenyloxazole (120 mg) in CC14 (30 mL) wasadded N-bromosuccinimide (1.9 g, 10.7 mmol) in portions. The reactionmixture was stirred at reflux for 2 h. After cooling to roomtemperature, the reaction mixture was diluted with EtOAc, filtered andconcentrated to give the crude product, which was used for the next stepwithout further purification. LC-MS: m/z 238 (M+H⁺).

(b) ((1-Oxo-1,2-dihydroisoquinolin-3-yl)methyl)triphenylphosphoniumbromide

A solution of 3-(bromomethyl)isoquinolin-1(2H)-one and PPh₃ (1.8 g, 6.87mmol) in 1,4-dioxane (50 mL) was refluxed for 2 h. After cooling to roomtemperature, the reaction mixture was filtered to give the desiredproduct (317 mg). LC-MS: m/z 420 (M+H⁺).

(c)(E,Z)-N,N-Dimethyl-2-(2-(1-oxo-1,2-dihydroisoquinolin-3-yl)vinyl)-4-phenyl-1H-imidazole-1-sulfonamide

2-Formyl-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (210 mg, 0.753mmol) and((1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)triphenylphosphonium bromide(317 mg, 0.635 mmol) were dissolved in CHCl₃ (10 mL). Sodium hydroxidesolution (2 mL, 50% w/w in H₂O) was added dropwise over 5 minutes andthe resulting solution was stirred at room temperature for 0.5 h beforediluting with H₂O (30 mL). The mixture was washed with CHCl₃ (50 mL×2),and the organic layer was dried over Na₂SO₄ and filtered. The filtratewas concentrated and purified by column chromatography to give thedesired product (80 mg). LC-MS: m/z 421 (M+H⁺).

(d) (E,Z)-3-(2-(4-Phenyl-1H-imidazol-2-yl)vinyl)isoquinolin-1(2H)-one

A solution of(E,Z)-N,N-dimethyl-2-(2-(1-oxo-1,2-dihydroisoquinolin-3-yl)vinyl)-4-phenyl-1H-imidazole-1-sulfonamide(80 mg, 0.19 mmol) and HCl (37% in water, 0.1 mL) in 1,4-dioxane (3 mL)was stirred at 90° C. for 2 h. After cooling to room temperature, thereaction mixture was filtered to give the desired product (40 mg).LC-MS: m/z 314 (M+H⁺).

(e) 3-(2-(4-Phenyl-1H-imidazol-2-yl)ethyl)isoquinolin-1(2H)-one

The title compound was prepared according to General Procedure A-(d).LC-MS: m/z 316 (M+H⁺).

5. General Procedure E

(a) ((4-Oxo-3,4-dihydroquinazolin-2-yl)methyl)triphenylphosphoniumchloride was prepared according to General Procedure D-(b). LC-MS: m/z421 (M+H⁺). (b) (E,Z)-2-(2-(5-Phenylthiophen-2-yl)vinyl)quinazolin-4(3H)-one was prepared according toGeneral Procedure D-(c). LC-MS: m/z 331 (M+H⁺). (c)2-(2-(5-Phenylthiophen-2-yl)ethyl)quinazolin-4(3H)-one was preparedaccording to General Procedure D-(e). LC-MS: m/z 333 (M+H⁺).

6. General Procedure F

(a) 2,4,5-Tribromo-1H-imidazole

To a solution of imidazole (60 g, 0.88 mol) in chloroform (360 mL) wasadded bromine (138 g, 1 mol) in chloroform (100 mL) dropwise at roomtemperature. Then the mixture was stirred for 1 h. After removing thesolvent, the residue was suspended in hot water, filtered and dried invacuo to provide 64 g of the desired product as a white solid. GC-MS:304 (M+H⁺).

(b) 5-Bromo-1H-imidazole

2,4,5-Tribromo-1H-imidazole (32 g, 0.105 mol) was refluxed with 20%aqueous sodium sulphite solution (66.34 g, 0.527 mol) for 8 h. The solidproduct precipitated upon cooling and was collected by vacuum filtrationto yield 12.5 g of the desired product. LC-MS: 147, 149 (M+H⁺).

(c) 4-Bromo-1-methyl-1H-imidazole

To a solution of 5-bromo-1H-imidazole (70 g, 0.48 mol) in THF (220 mL)in an ice bath was added 25% NaOH (70 mL). MeI (81 g, 0.57 mol) was thenadded dropwise at 7-8° C.

The mixture was stirred at ambient temperature for 5 min, and then thesolvent was removed under reduced pressure. The title compound (15 g)was obtained by fractional distillation. GC-MS: 160 (M⁺).

(d) 4-Bromo-1-methyl-1H-imidazole-2-carbaldehyde

The title compound was prepared according to General Procedure A-(b).GC-MS: 188 (M⁺).

(e) 2-((E,Z)-2-(4-Bromo-1-methyl-1H-imidazol-2-yl)vinyl)quinoline

The title compound was prepared according to General Procedure A-(c).LC-MS: m/z 314 (M+H⁺).

(f) 2-(2-(4-Bromo-1-methyl-1H-imidazol-2-yl)ethyl)quinoline

To a solution of2-((E,Z)-2-(4-bromo-1-methyl-1H-imidazol-2-yl)vinyl)quinoline (8.3 g,26.4 mmol) in MeOH (150 mL) and THF (150 mL) was added 1 g of Raney-Nicatalyst and the mixture was stirred under hydrogen atmosphere for 2 h.The catalyst was then filtered off and the filtrate was concentrated andpurified by column chromatography to afford 3.8 g of the desired productas a solid. LC-MS: m/z 316 (M+H⁺).

(g) 2-(2-(1-Methyl-4-(thiophen-3-yl)-1H-imidazol-2-yl)ethyl)quinoline

A suspension of 2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)ethyl)quinoline(0.31 g, 0.980 mmol), thiophen-3-ylboronic acid (0.25 g, 1.960 mmol),and Pd(PPh₃)₄ (0.022 g, 0.441 mmol) in 1,4-dioxane (6 mL) under N₂ wasstirred at room temperature for 0.5 h and then Na₂CO₃ (0.3105 g, 2.94mmol) in water (1 mL) was added. The mixture was refluxed overnight. Themixture was then cooled to room temperature and partitioned betweenwater and ethyl acetate (EtOAc). The separated organic layer was dried,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography to afford 55.6 mg of the desiredcompound. LC-MS: m/z 320 (M+H⁺).

7. General Procedure G

(a) 1-(4-Methoxybenzyl)-4-bromo-1H-imidazole

To a suspension of 5-bromo-1H-imidazole (10 g, 68.5 mmol) and K₂CO₃(37.8 g, 274 mmol) in DMF (100 mL) was added1-(chloromethyl)-4-methoxybenzene (11.8 g, 75.4 mmol) dropwise at roomtemperature. The resulting mixture was stirred for 16 hours, and thendichloromethane (DCM) was added. The mixture was successively washedwith water and brine, dried and concentrated to give a residue that waspurified by column chromatography to afford 12.3 g of the desiredcompound as a solid. LC-MS: m/z 267 (M+H⁺).

(b) 1-(4-Methoxybenzyl)-4-bromo-1H-imidazole-2-carbaldehyde

The title compound was prepared according to General Procedure A-(b).LC-MS: m/z 295 (M+H⁺).

(c)2-((E,Z)-2-(1-(4-Methoxybenzyl)-4-bromo-1H-imidazol-2-yl)vinyl)quinoline

The title compound was prepared according to General Procedure A-(c).LC-MS: m/z 420 (M+H⁺).

(d) 2-((E,Z)-2-(4-Bromo-1H-imidazol-2-yl)vinyl)quinoline

A solution of2-((E,Z)-2-(1-(4-methoxybenzyl)-4-bromo-1H-imidazol-2-yl)vinyl)quinoline(8.5 g, 0.02 mol) in CH₃SO₃H (70 mL) was refluxed overnight. Aftercooling to room temperature, the reaction mixture was diluted with water(200 mL) and the pH was adjusted to 8-9 with aqueous Na₂CO₃. Theresulting solid was filtered and purified by column chromatography toafford the desired product (4.3 g). LC-MS: m/z 300 (M+H⁺).

(e) 2-(2-(4-Bromo-1H-imidazol-2-yl)ethyl)quinoline

The title compound was prepared according to General Procedure F-(f).LC-MS: m/z 302 (M+H⁺).

(f) 2-(2-(4-(Pyridin-4-yl)-1H-imidazol-2-yl)ethyl)quinoline

The title compound was synthesized according to General Procedure F-(g).LC-MS: m/z 301 (M+H⁺).

8. General Procedure H

(a) Quinoxaline-2-carbaldehyde

To a solution of SeO₂ (2.3 g, 20.9 mmol) and water (1 mL) in 1,4-dioxane(25 mL) at reflux was added 2-methylquinoxaline (2 g, 13.9 mmol) in1,4-dioxane (4 mL). After refluxing for 4 h, the reaction mixture wasfiltered. The filtrate was concentrated and purified by columnchromatography to give 500 mg of the desired product. LC-MS: m/z 159(M+H⁺).

(b) (E,Z)-2-(2-(1-Phenyl-1H-pyrazol-3-yl)vinyl)quinoxaline

The title compound was synthesized according to General Procedure D-(c).LC-MS: m/z 299 (M+H⁺).

(c) 2-(2-(1-Phenyl-1H-pyrazol-3-yl)ethyl)quinoxaline

The title compound was synthesized according to General Procedure A-(d).LC-MS: m/z 301(M+H⁺).

9. General Procedure I

(a) 2-Phenyloxazole

To a solution of oxazole (0.5 g, 7 mmol) in anhydrous THF (10 mL) wasadded n-BuLi (3.5 mL, 8.8 mmol) dropwise at −65° C. After stirring for10 min, anhydrous ZnCl₂ (2 g, 14.7 mmol) was added. The reaction mixturewas allowed to warm to room temperature. Then Pd(PPh₃)₄ (0.3 g, 0.26mmol) and iodobenzene (2 g, 9.8 mmol) were added. The reaction mixturewas heated at 60° C. for 1 h. After quenching with water (20 mL), thesolution was extracted with EtOAc (20 mL×3). The combined organic layerswere dried over Na₂SO₄ and filtered. The filtrate was concentrated andpurified by column chromatography to give 600 mg of the desired product.LC-MS: m/z 146 (M+H⁺).

(b) 2-Phenyloxazole-5-carbaldehyde

To a 50 mL flask charged with DMF (5 mL) was added POCl₃ (0.7 g, 4.6mmol) dropwise at 0° C. After stirring for 10 min, a solution of2-phenyloxazole (0.6 g, 4.1 mmol) in DMF (5 mL) was added dropwise. Thereaction mixture was heated to 100° C. and stirred for 48 h. Aftercooling to room temperature, the reaction mixture was poured into icewater and the pH was adjusted to 10 with 10% aqueous NaOH. The aqueousmixture was extracted with EtOAc (20 mL×3). The combined organic layerswere dried over Na₂SO₄ and filtered. The filtrate was concentrated andpurified by column chromatography to give 240 mg of the desired product.LC-MS: m/z 174 (M+H⁺).

(c) (E,Z)-2-Phenyl-5-(2-(quinoxalin-2-yl)vinyl)oxazole

The title compound was prepared according to General Procedure A-(c).LC-MS: m/z 300 (M+H⁺).

(d) 2-Phenyl-5-(2-(quinoxalin-2-yl)ethyl)oxazole

The title compound was prepared according to General Procedure A-(d).LC-MS: m/z 302 (M+H⁺).

10. General Procedure J

(a) 6-Phenylpicolinaldehyde was prepared according to General ProcedureF-(g). GC-MS: 183 (M⁺). (b)(E,Z)-2-(2-(6-Phenylpyridin-2-yl)vinyl)quinoxaline was preparedaccording to General Procedure A-(c). LC-MS: m/z 310 (M+H⁺). (c)2-(2-(6-Phenylpyridin-2-yl)ethyl)quinoxaline was prepared according toGeneral Procedure A-(d). LC-MS: m/z 312 (M+H⁺).

11. General Procedure K

(a) 2-(2-Chloroacetamido)benzoic acid

The title compound was synthesized according to General Procedure C-(a).LC-MS: m/z 214 (M+H⁺).

(b) (2-(2-Carboxyphenylamino)-2-oxoethyl)triphenylphosphonium chloride

The title compound was prepared according to General Procedure D-(b).LC-MS: m/z 440 (M+H⁺).

(c)(E,Z)-2-(3-(1-(N,N-Dimethylsulfamoyl)-4-phenyl-1H-imidazol-2-yl)acrylamido)benzoicacid

The title compound was prepared according to General Procedure D-(c).LC-MS: m/z 441 (M+H⁺).

(d)2-(3-(1-(N,N-Dimethylsulfamoyl)-4-phenyl-1H-imidazol-2-yl)propanamido)benzoicacid

The title compound was prepared according to General Procedure A-(d).LC-MS: m/z 443 (M+H⁺).

(e)N,N-Dimethyl-2-(2-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)ethyl)-4-phenyl-1H-imidazole-1-sulfonamide

A solution of2-(3-(1-(N,N-dimethylsulfamoyl)-4-phenyl-1H-imidazol-2-yl)propanamido)benzoicacid (150 mg, 0.339 mmol) in Ac₂O (10 mL) was stirred at reflux for 5 h.The reaction mixture was then concentrated to give a white solid (100mg), which was used for the next step without further purification.LC-MS: m/z 425 (M+H⁺).

(f) 2-(2-(4-Phenyl-1H-imidazol-2-yl)ethyl)-4H-benzo[d][1,3]oxazin-4-one

The title compound was prepared according to General Procedure D-(d).LC-MS: m/z 318 (M+H⁺).

12. General Procedure L

General Procedure L-1

General Procedure L-2

(a) Quinoline-5,6-diamine

To a solution of 5-amine-6-nitroquinoline (500 mg, 2.7 mmol) in ethanol(20 mL) was added hydrazine hydrate (200 mg, 4 mmol) at roomtemperature. Then Raney Ni was added dropwise until the reaction mixturebecame clear. The mixture was filtered and the filtrate was collectedand concentrated to obtain quinoline-5,6-diamine as a green solid (430mg), which was used for the next step without further purification. MS(ESI) m/z 159 (M+H⁺).

(b) N-(5-Aminoquinolin-6-yl)-3-(quinolin-2-yl)propanamide andN-(6-Aminoquinolin-5-yl)-3-(quinolin-2-yl)propanamide

To a solution of 3-(quinoxalin-2-yl)propanoic acid (550 mg, 2.7 mmol) inDCM (30 mL) was added HOBt (550 mg, 4 mmol) and EDCI (780 mg, 4 mmol).After stirring for 30 minutes, quinoline-5,6-diamine (430 mg, 2.7 mmol)was added and the reaction was stirred for 3 hours. The mixture waswashed with water (10 mL) and extracted with DCM (30 mL×3).

The combined organic layers were dried over sodium sulfate, filtered,and concentrated to afford a yellow mixture which was purified byreverse phase chromatography.N-(5-Aminoquinolin-6-yl)-3-(quinoxalin-2-yl)propanamide (180 mg) andN-(6-aminoquinolin-5-yl)-3-(quinoxalin-2-yl)propanamide (80 mg) wereisolated. MS (ESI) m/z 343 (M+H⁺).

(c) 2-(2-(Quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline

N-(5-Aminoquinolin-6-yl)-3-(quinoxalin-2-yl)propanamide (180 mg, 0.5mmol) or N-(6-aminoquinolin-5-yl)-3-(quinoxalin-2-yl)propanamide (80 mg,0.23 mmol) in acetic acid (5 mL or 2 mL, respectively) was heated to 60°C. and stirred for 2 hours. Excess acetic acid was removed under vacuum,and the residue was purified by column chromatography to afford2-(2-(quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline (150 mg) and2-(2-(quinoxalin-2-yl)ethyl)-1H-imidazo[4,5-f]quinoline (60 mg). MS(ESI) m/z 325 (M+H⁺).

(d) 3-Methyl-2-(2-(quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline and1-Methyl-2-(2-(quinoxalin-2-yl)ethyl)-1H-imidazo[4,5-f]quinoline

To a solution of 2-(2-(quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline(100 mg, 0.31 mmol) or2-(2-(quinoxalin-2-yl)ethyl)-1H-imidazo[4,5-f]quinoline (60 mg, 0.18mmol) in DMF (3 mL or 2 mL, respectively) cooled in an ice bath wasadded sodium hydride (12 mg, 0.31 mmol; or 7 mg, 0.18 mmol;respectively). After stirring for 30 minutes, iodomethane (44 mg, 0.31mmol; or 25 mg, 0.18 mmol; respectively) was added and the mixture wasstirred at room temperature for 2 hours. The reaction was quenched withwater, washed with saturated sodium bicarbonate (10 mL), and extractedwith DCM (20 mL×3). The combined organic layers were dried andconcentrated to give a yellow solid as the free base. The free base mayoptionally be converted to a salt. For example, the free base wasstirred in an HCl in methanol solution for 30 minutes to afford3-methyl-2-(2-(quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-f]quinolinehydrochloride (20 mg) or1-methyl-2-(2-(quinoxalin-2-yl)ethyl)-1H-imidazo[4,5-f]quinolinehydrochloride (25 mg) as a pale yellow solid.

13. General Procedure M

(a) (E/Z)-2-(2-(Benzo[d]oxazol-2-yl)vinyl)quinazolin-4(3H)-one wasprepared according to General Procedure A-(c) and heating in a microwavereactor. MS (ESI) m/z 290 (M+H⁺). (b)2-(2-(Benzo[d]oxazol-2-yl)ethyl)quinazolin-4(3H)-one was preparedaccording to General Procedure A-(d) with methanol/THF as solvent. MS(ESI) m/z 292 (M+H⁺).

14. Preparation of Aldehyde Intermediates

(a) (E)-2-(Benzo[d]oxazol-2-yl)-N,N-dimethylethenamine

A mixture of 2-methylbenzo[d]oxazole (3 g, 22.6 mmol) in DMF (3.2 g) anddimethyl acetamide (3.5 g, 29.3 mmol) was stirred under N₂ at 145° C.overnight. Then the solution was poured into ice-water and extractedwith EtOAc (100 mL×2). The organic phase was washed, dried andconcentrated. The residue was purified by column chromatography to getthe title compound (2.2 g). MS (ESI) m/z 134 (M+H⁺).

(b) Benzo[d]oxazole-2-carbaldehyde

To (E)-2-(benzo[d]oxazol-2-yl)-N,N-dimethylethenamine (1 g, 5.32 mmol)in THF (15 mL) at 0° C. was added water (15 mL) and NaIO₄ (3.4 g, 16mmol). The resulting mixture was stirred at 0° C. for 10 min, then atroom temperature for 2 h. To the solution was added H₂O and EtOAc andthen the mixture was filtered. The clear solution was extracted withEtOAc and the organic phase was washed with aqueous NaHCO₃ solution. Theorganic phase was concentrated and the residue was purified by columnchromatography to give the title compound (120 mg). MS (ESI) m/z 148(M+H⁺).

(c) 4,5-Diphenyloxazole

A mixture of benzoin (2.65 g, 12.5 mmol), formamide (10 mL), xylene (40mL) and cone. H₂SO₄ (1 mL) was refluxed for 14 h with a dean-stark trapattached to remove water. After cooling to room temperature, water wasadded to the mixture. The organic layer was separated, washed, dried(with MgSO₄), and then distilled under reduced pressure to give4,5-diphenyloxazole (1.93 g) as a yellow solid.

(d) 4,5-Diphenyloxazole-2-carbaldehyde

n-BuLi (361 mg, 5.65 mmol) was added to a stirred and cooled (−78° C.)solution of 4,5-diphenyloxazole (500 mg, 2.26 mmol) in dry THF. Thestirring was continued for 30 min at −78° C., andN-methyl-N-(pyridin-2-yl)formamide (461 mg, 3.39 mmol) was added. Theresulting solution was stirred at −78° C. for 1 h, then quenched withH₂O. The mixture was extracted with EtOAc (3×20 mL), and the combinedorganic extracts were dried (MgSO₄) and concentrated. The crude productwas purified by column chromatography to afford the desired product4,5-diphenyloxazole-2-carbaldehyde (372 mg) as an orange oil.

(e) 5-Phenyloxazole

A mixture of benzaldehyde (3 g, 28.3 mmol),1-(isocyanomethylsulfonyl)-4-methylbenzene (5.5 g, 28.3 mmol) and K₂CO₃(5.9 g, 42.5 mmol) in 60 mL methanol was refluxed for 2 h and thenconcentrated. 250 mL EtOAc was added and the mixture was washed withwater and brine, dried, and concentrated to give 5-phenyl oxazole (3.4g). MS (ESI) m/z 145 (M+H⁺).

(f) 5-Phenyloxazole-2-carbaldehyde

The title compound was synthesized according to Synthetic Procedure14-(d). MS (ESI) m/z 174 (M+H⁺).

(g) (Z)-Benzaldehyde oxime

To a stirred solution of benzaldehyde (3 g, 28.3 mmol) in ethanol (50mL) and water (30 mL), NH₂OH hydrochloride (3.9 g, 56.6 mmol) and sodiumhydroxide (2.26 g, 56.6 mmol) were added. The mixture was heated atreflux for 6 hours. The resulting mixture was cooled to room temperatureand extracted with EtOAc, and the organic layer was dried over anhydroussodium sulfate. The solution was then concentrated under vacuum to givethe title compound as an oil-like solid (3.4 g), which was used in thenext step without further purification. MS (ESI) m/z 121 (M+H⁺).

(h) (3-Phenylisoxazol-5-yl)methanol

(Z)-Benzaldehyde oxime (3.4 g, 28.2 mmol) was dissolved in anhydrous THF(50 mL) and cooled to 0° C. N-Chlorosuccinimide (5.63 g, 42.3 mmol) andpyridine (221 mg, 2.8 mmol) were added and the mixture was stirred atroom temperature for 1 hour. Prop-2-yn-1-ol (1.89 g, 33.4 mmol) and NEt₃(286 mg, 2.8 mmol) were added and the mixture was heated at reflux for 2hours. The reaction was cooled and quenched with water, extracted withEtOAc and dried over anhydrous sodium sulfate. The solution wasconcentrated under vacuum to give a crude product, which was purified bycolumn chromatography to afford (3-phenylisoxazol-5-yl)methanol as awhite solid (1.8 g).

(i) 3-Phenylisoxazole-5-carbaldehyde

To (3-phenylisoxazol-5-yl)methanol (0.9 g, 5.1 mmol) in DCM (10 mL) wasadded pyridinium chlorochromate (PCC) (2.1 g, 10.2 mmol) and the mixturewas stirred at room temperature for 2 hours. The reaction was quenchedwith water, extracted with EtOAc and dried over anhydrous sodiumsulfate. The solution was then concentrated under vacuum to give3-phenylisoxazole-5-carbaldehyde as a light yellow solid (600 mg).

(j) Benzo[d]thiazole-2-carbaldehyde

To a solution of benzo[d]thiazole (1 g, 7 mmol) in DMF (10 mL) was addedn-BuLi (8.4 mL, 21 mmol) over 15 min at −78° C. and the mixture wasstirred at this temperature for 1 hour. The reaction was quenched withwater, extracted with EtOAc and dried over anhydrous sodium sulfate. Thesolution was then concentrated under vacuum to givebenzo[d]thiazole-2-carbaldehyde as a light yellow solid (500 mg).

(k) Ethyl 4-phenylthiazole-2-carboxylate

To ethyl 2-amino-2-thioxoacetate (4 g, 30 mmol) in ethanol (50 mL) wasadded pyridine (0.24 g, 3 mmol). 2-Bromo-1-phenylethanone (5 g, 25 mmol)was added after 10 minutes and the mixture was then heated at reflux for6 hours. The resulting mixture was washed with water and extracted withEtOAc and dried over anhydrous sodium sulfate. The solution was thenconcentrated under vacuum to give a crude product, which was purified bycolumn chromatography to afford the title compound as a white solid (4.4g). MS (ESI) m/z 233 (M+H⁺).

(l) (4-Phenylthiazol-2-yl) methanol

To ethyl 4-phenylthiazole-2-carboxylate (1 g, 4.3 mmol) in anhydrous THFwas added LiAlH₄ and the mixture was stirred for 1 hour. The reactionwas quenched with water, extracted with EtOAc and dried over anhydroussodium sulfate. The solution was concentrated under vacuum to afford(4-phenylthiazol-2-yl)methanol as a white solid (0.9 g). MS (ESI) m/z191 (M+H⁺).

(m) 4-Phenylthiazole-2-carbaldehyde

To (4-phenylthiazol-2-yl)methanol (900 mg, 4.7 mmol) in DCM (10 mL) wasadded MnO₂ (4 g, 47 mmol), and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was then filtered, washedwith water, extracted with EtOAc and dried over anhydrous sodiumsulfate. The solution was concentrated under vacuum to give a crudeproduct, which was purified by column chromatography to afford the titlecompound as a yellow solid (360 mg).

(n) 4-Phenyl-1-trityl-1H-imidazole

A solution of 5-phenyl-1H-imidazole (504 mg, 3.5 mmol) in DMF (10 mL)was cooled to 0° C., and then NEt₃ (530 mg, 5.25 mmol) was added,followed by the addition of (chloromethanetriyl)tribenzene (1.17 g, 4.2mmol) in small portions. The resulting slurry was stirred at roomtemperature for 2 hours. The mixture was poured into ice-water (50 mL)and stirred until the ice melted. The resulting precipitate wascollected and dissolved in DCM (100 mL). The solution was dried oversodium sulfate, filtered, concentrated and then purified by columnchromatography to obtain 4-phenyl-1-trityl-1H-imidazole as a white solid(1.0 g). MS (ESI): m/z 387 (M+H)⁺.

(o) 4-Phenyl-1-trityl-1H-imidazol-2-carbaldehyde

The title compound was prepared according to Synthetic Procedure 14-(j).MS (ESI): m/z 415 (M+H)⁺.

(p) 4-Phenyl-1H-imidazole-2-carbaldehyde

To a solution of 4-phenyl-1-trityl-1H-imidazole-2-carbaldehyde (414 mg,1 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL).After stirring at room temperature for 30 minutes, the solvent wasremoved in vacuo. The resulting residue was diluted with DCM (50 mL) andsaturated sodium bicarbonate (50 mL). The aqueous layer was extractedwith DCM (2×50 mL). The combined organic layers were dried over sodiumsulfate, filtered, concentrated and then purified by columnchromatography to give 4-phenyl-1H-imidazole-2-carbaldehyde as a whitesolid (160 mg). MS (ESI): n/z 173 (M+H)⁺.

(q) 1-(4-Bromobutyl)-4-phenyl-1H-imidazole-2-carbaldehyde

A mixture of 4-phenyl-1H-imidazole-2-carbaldehyde (1.79 g, 10.4 mmol),potassium carbonate (2.87 g, 20.8 mmol), potassium iodide (2.94 g, 17.7mmol) and 1,4-dibromobutane (4.49 g, 20.8 mmol) in dry DMF (35 mL) wereheated to 50° C. and stirred for 4 hours. The mixture was poured intoice-water (100 mL), and washed with EtOAc (2×80 mL). The combinedorganic layers were washed with brine (2×100 mL). The organic layer wasdried over sodium sulfate, filtered, concentrated and then purified bycolumn chromatography to give1-(4-bromobutyl)-4-phenyl-1H-imidazole-2-carbaldehyde as a colorless oil(2.1 g). MS (ESI): m/z 308 (M+H)⁺.

(r) 1-Phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carbaldehyde

A solution of 1-(4-bromobutyl)-4-phenyl-1H-imidazole-2-carbaldehyde (918mg, 3 mmol) in dry acetonitrile (300 mL) was heated at reflux.(E)-2,2′-(Diazene-1,2-diyl)bis(2-methylbutanenitrile) (AIBN) (288 mg,1.5 mmol) was added followed by addition of tributylstannane (1.93 g,6.6 mmol) over the course of 2 hours. An additional aliquot of AIBN (288mg, 1.5 mmol) was added 1 hour after the start of the reaction. Themixture was stirred under reflux for 2 hours. Acetonitrile was removedunder reduced pressure. The obtained residue was purified by columnchromatography to give1-phenyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-3-carbaldehyde as awhite solid (250 mg). MS (ESI): m/z 227 (M+H⁺).

(s) 4-(5-(Prop-2-ynylthio)-4H-1,2,4-triazol-3-yl)pyridine

A mixture of 3-(pyridin-4-yl)-1H-1,2,4-triazole-5(4H)-thione (2 g, 11.2mmol), 3-bromoprop-1-yne (1.47 g, 12.3 mmol) and sodium acetate (5.34 g,65.1 mmol) in DMF (20 mL) was stirred for 6 h at room temperature. Thereaction mixture was then poured into water (50 mL) and extracted withDCM. The combined organic layers were washed with water three times,dried with Na₂SO₄, filtered and concentrated to obtain the titlecompound (1.5 g).

(t) 4-(4H-1,2,4-Triazol-3-yl)pyridine

A mixture of 4-(5-(prop-2-ynylthio)-4H-1,2,4-triazol-3-yl)pyridine (1.6g, 7.4 mmol) and Raney Ni in ethanol (30 mL) was stirred at reflux for 8h. The reaction mixture was then filtered through a Celite pad and thesolution was concentrated to obtain the crude compound. The crudeproduct was purified by column chromatography to give4-(4H-1,2,4-triazol-3-yl)pyridine (0.4 g).

(u) 4-(4-(4-Methoxybenzyl)-4H-1,2,4-triazol-3-yl)pyridine

A mixture of 4-(4H-1,2,4-triazol-3-yl)pyridine (0.56 g, 3.8 mmol), PMBCl(0.66 g, 4.2 mmol), and K₂CO₃ (2.12 g, 15.3 mmol) in DMF (10 mL) wasstirred for 4 h at room temperature. The reaction mixture was thendiluted with water and extracted with DCM. The combined organic layerswere washed with water three times, dried with Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography togive 4-(4-(4-methoxybenzyl)-4H-1,2,4-triazol-3-yl)pyridine (0.60 g).

(v)(4-(4-Methoxybenzyl)-5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)methanediol

The title compound was prepared according to Synthetic Procedure 14-(j).

15. 2-(2-(Quinoxalin-2-yl)ethyl)benzo[d]thiazole

A mixture of 3-(quinoxalin-2-yl)propanoic acid (530 mg, 2.6 mmol) and2-aminobenzenethiol (390 mg, 3.12 mmol) in PPA (7 g) was heated to 120°C. and stirred for 10 minutes. The reaction mixture was cooled andaqueous NaOH (20 mL) was added. The mixture was extracted with DCM (2×20mL). The combined organic layers were dried over sodium sulfate,filtered, concentrated and then purified by prep-TLC to give2-(2-(quinoxalin-2-yl) ethyl)benzo[d]thiazole as a yellow solid. (38mg). MS (ESI) m/z 318 (M+H⁺).

16. 1,2-Di(quinoxalin-2-yl)ethane

(a) 1,2-Di(quinoxalin-2-yl)ethanol

A solution of 2-methyl quinoxaline (0.11 g, 0.76 mmol) andquinoxaline-2-carbaldehyde (0.16 g, 0.63 mmol) in AcOH (2 mL) wasstirred for 1 hour at 70° C. The reaction mixture was concentrated andpurified with reverse phase column chromatography to afford1,2-di(quinoxalin-2-yl)ethanol (0.05 g) as a yellow solid. MS (ESI) m/z303.1 (M+H⁺).

(b) 2,2′-(1-Chloroethane-1,2-diyl)diquinoxaline

A solution of 1,2-di(quinoxalin-2-yl)ethanol (0.05 g, 0.166 mmol) inSOCl₂ (2 mL) was stirred at room temperature for 1 hour. The solutionwas then concentrated to afford2,2′-(1-chloroethane-1,2-diyl)diquinoxaline (0.05 g) as a yellow solid.MS (ESI) m/z 321.1 (M+H⁺).

(c) 1,2-Di(quinoxalin-2-yl)ethane

The title compound was prepared according to General Procedure A-(d). MS(ESI) m/z 287.1 (M+H⁺).

17. 2-(2-(Imidazo[1,2-a]pyridin-2-yl)ethyl)quinoxaline

(a) (Imidazo[1,2-a]pyridin-2-ylmethyl)triphenylphosphonium chloride wasprepared according to General Procedure D-(b). MS (ESI) m/z 393 (M+H⁺).(b) (E/Z)-2-(2-(Imidazo[1,2-a]pyridin-2-yl)vinyl)quinoxaline wasprepared according to General Procedure D-(c). MS (ESI) m/z: 272.32(M+H⁺). (c) 2-(2-(Imidazo[1,2-a]pyridin-2-yl)ethyl)quinoxaline wasprepared according to General Procedure A-(d). MS (ESI) m/z 274.32(M+H⁺).

18. 2-((4-Phenyl-1H-imidazol-2-yl)methoxy) quinoxaline

(a) 2-(Hydroxymethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide

2-Formyl-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (221 mg, 0.79mmol) was dissolved in anhydrous MeOH (10 mL) and NaBH₄ (89 mg, 2.37mmol) was added in portions. Gas evolved and the suspension was stirredat room temperature. After 30 min, the crude reaction mixture was pouredinto H₂O and extracted with EtOAc (3×20 mL). The combined organic layerswere washed with brine, dried (Na₂SO₄), filtered and concentrated togive crude2-(hydroxymethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide,which was used directly in the next reaction.

(b)N,N-Dimethyl-4-phenyl-2-((quinoxalin-2-yloxy)methyl)-1H-imidazole-1-sulfonamide

2-(Hydroxymethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (0.79mmol) was dissolved in anhydrous DMF (5 mL) and cooled to 0° C. NaH (60%dispersion in mineral oil, 47 mg, 1.19 mmol) was added and thesuspension was stirred for 2 min. 2-Chloroquinoxaline (195 mg, 1.19mmol) in anhydrous DMF (3 mL) was added dropwise and the resultingsuspension was allowed to warm to room temperature. After 2 h, MeOH (10mL) was added slowly. The crude reaction mixture was poured into H₂O O(30 mL) and extracted with Et₂O (3×30 mL). The combined organic layerswere washed with brine, dried (Na₂SO₄), filtered and concentrated togive crudeN,N-dimethyl-4-phenyl-2-((quinoxalin-2-yloxy)methyl)-1H-imidazole-1-sulfonamide,which was used directly in the next reaction.

(c) 2-((4-Phenyl-1H-imidazol-2-yl)methoxy)quinoxaline

The title compound was prepared according to General Procedure D-(d).LC-MS m/z 303 (M+H⁺).

19. 2-(4-Phenyl-1H-imidazol-2-ylthio)quinoxaline

1H-Imidazole-2(3H)-thione (241 mg, 0.92 mmol) and 2-chloroquinoxaline(166 mg, 1.01 mmol) were combined in anhydrous THF (10 mL) in amicrowave vial. To the suspension was added Hunig's base (320 μL, 1.84mmol). The resulting clear yellow solution was heated in the microwave(130° C., 30 min), then concentrated and purified by columnchromatography. 2-(4-Phenyl-1H-imidazol-2-ylthio)quinoxaline wasobtained as a yellowish oil. LC-MS m/z 305 (M+H⁺).

20. N-((4-Phenyl-1H-imidazol-2-yl)methyl)quinoxalin-2-amine

(a) Benzyl(1-(N,N-dimethylsulfamoyl)-4-phenyl-1H-imidazol-2-yl)methylcarbamate

The title compound was prepared according to Kitigawa et al., J. Med.Chem., 2007, 50, 4710.

(b) 2-(Aminomethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide

Benzyl(1-(N,N-dimethylsulfamoyl)-4-phenyl-1H-imidazol-2-yl)methylcarbamate(235 mg, 0.56 mmol) was dissolved in anhydrous DMF (5 mL) and Pd oncarbon (about 5 mg, catalytic) was added. The vessel containing thesolution was purged with H₂, and the vessel was sealed. A H₂ balloon wasattached. Another 10 mg of Pd on carbon was added after 8 h, and thesuspension was stirred at room temperature for 48 hours (total). Thesuspension was filtered through Celite, washing with EtOAc (30 mL), andthe washes were concentrated to give crude2-(aminomethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide.

(c)N,N-Dimethyl-4-phenyl-2-((quinoxalin-2-ylamino)methyl)-1H-imidazole-1-sulfonamide

2-(Aminomethyl)-N,N-dimethyl-4-phenyl-1H-imidazole-1-sulfonamide (0.56mmol), 2-chloroquinoxaline (138 mg, 0.84 mmol), and Hunig's base (195 L,1.12 mmol) were dissolved in anhydrous THF (4.5 mL) in a microwave vial.The vial was heated in the microwave (180° C., 40 min), then poured intosaturated aqueous K₂CO₃ solution (50 mL). The layers were separated andthe aqueous phase was extracted with EtOAc (3×30 mL). The combinedorganic phases were washed with saturated aqueous NaCl (1×50 mL), dried(Na₂SO₄), filtered and concentrated to giveN,N-dimethyl-4-phenyl-2-((quinoxalin-2-ylamino)methyl)-1H-imidazol-1-sulfonamide.

(d) N-((4-Phenyl-1H-imidazol-2-yl)methyl)quinoxalin-2-amine

N,N-Dimethyl-4-phenyl-2-((quinoxalin-2-ylamino)methyl)-1H-imidazole-1-sulfonamidewas dissolve in MeOH (5 ml) and 1 M HCl aqueous solution (4.5 ml) wasadded. The suspension was heated in the microwave (120° C., 40 min) andthen poured into a separatory funnel. The phases were separated and theaqueous phase (pH about 2) was washed with Et₂O (2×20 mL). The combinedorganic layers were discarded and the aqueous phase was made basic (pHabout 10) by the slow addition of saturated aqueous K₂CO₃ (10 mL). Thebasic aqueous phase was extracted with EtOAc (3×40 mL). The combinedorganic phases were washed with saturated aqueous NaCl (1×50 mL), dried(Na₂SO₄), filtered and concentrated to give crudeN-((4-phenyl-1H-imidazol-2-yl)methyl)quinoxalin-2-amine. The materialwas purified by reverse phase HPLC (Gilson) to giveN-((4-phenyl-1H-imidazol-2-yl)methyl)quinoxalin-2-amine as a clear oil.LC-MS m/z 302 (M+H⁺).

21. 2-(2-(1H-Benzo[d]imidazol-2-yl)ethyl)-3-methylquinoxaline

3-(3-Methylquinoxalin-2-yl)propanoic acid (98 mg, 0.45 mmol) andbenzene-1,2-diamine (98 mg, 0.45 mmol) were suspended in 4 M HCl in1,4-dioxane (6 mL) and heated in the microwave (150° C., 2.5 h). Thecrude reaction was poured into saturated aqueous Na₂CO₃ solution (30 mL)and extracted with EtOAc (3×50 mL). The organic layers were combined,washed with brine (1×50 mL), dried (Na₂SO₄), filtered and concentrated.The crude material was purified by RPLC (Gilson). Fractions containingthe compound were combined, diluted with EtOAc and washed with saturatedaqueous Na₂CO₃, dried (Na₂SO₄), filtered and concentrated to give2-(2-(1H-benzo[d]imidazol-2-yl)ethyl)-3-methylquinoxaline (8 mg) as anorange oil. LC-MS m/z 289 (M+H⁺).

22. 2-((4-Phenyl-1H-imidazol-2-yloxy)methyl)quinoxaline and2-((4-phenyl-1H-imidazol-2-ylthio)methyl)quinoxaline

The title compounds were prepared according to Synthetic Procedure 19.Purification by reverse phase HPLC provided the title compounds as oils.

23. General Procedure N;2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline(Compound 125)

(a) O-(Mesitylsulfonyl)hydroxylamine

To a solution of 2,4,6-trimethylbenzene-1-sulfonyl chloride (30 g, 0.148mol) and tert-butyl hydroxycarbamate (18 g, 0.148 mol) in ether (500mL), was added Et₃N (15 g, 0.148 mol) dropwise over 1 h. The reactionmixture was stirred at room temperature for 4 h, then filtered. Thefiltrate was then concentrated under reduced pressure. The product waspurified by column to give tert-butyl mesitylsulfonyloxycarbamate as awhite solid (31 g). MS (ESI): m/z 338 [M+Na]⁺.

A solution of tert-butyl mesitylsulfonyloxycarbamate (3 g, 9.5 mmol) intrifluoroacetic acid (7 mL) was stirred at 10° C. for 40 min, thenpoured into ice/water (10 mL) and the resulting solid was collected byfiltration. The solid was dissolved in DCM (12 mL), dried with Na₂SO₄,and filtered. The solution containing O-(mesitylsulfonyl) hydroxylaminewas used without further purification.

(b) 3,6-Dimethylpyrazin-2-amine

A mixture of 2,5-dimethylpyrazine (14 g, 0.13 mol) inN,N-dimethylaniline (50 mL) was heated to 170° C. and NaNH₂ (22 g, 0.56mol) was added in portions. The reaction mixture was stirred at 170° C.for 1 h, and the solvent was removed. The product was purified by columnchromatography to give 3,6-dimethylpyrazin-2-amine as a brown solid (1.6g). MS (ESI): m/z 124[M+H]⁺.

(c) 1-Amino-3,6-dimethylpyrazin-2(1H)-iminium2,4,6-trimethylbenzenesulfonate

A mixture of 3,6-dimethylpyrazin-2-amine (1.23 g, 10 mmol) in DCM (20mL) was cooled to 0° C. and a solution ofO-(mesitylsulfonyl)hydroxylamine (4.3 g, 20 mmol) was added slowly. Thereaction mixture was allowed to warm to room temperature, stirred for 3h and then filtered. The solid collected was washed with DCM (50 mL) togive 1-amino-3,6-dimethylpyrazin-2(1H)-iminium2,4,6-trimethylbenzenesulfonate as a brown solid (2.0 g). MS (ESI): m/z139[M-199]⁺.

(d) 2-(Chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine

A mixture of 1-amino-3,6-dimethylpyrazin-2(1H)-iminium2,4,6-trimethylbenzenesulfonate (2.0 g, 5.9 mmol) and sodium hydroxide(480 mg, 12 mmol) in ethanol (20 mL) was stirred at 60 OC for 1 h;methyl 2-chloroacetate (1.34 g, 12.4 mmol) was then added slowly. Thereaction mixture heated at reflux for 4 h, then the solvent was removed.The product was purified by column chromatography to give2-(chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine as a yellowsolid (420 mg). MS (ESI): m/z 197[M+H]⁺.

(e)((5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphoniumchloride

The title compound was prepared according to General Procedure D-(b). MS(ESI): m/z 424[M-35]⁺.

(f)(E)-2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)quinoline

The title compound was prepared according to General Procedure D-(c) togive the compound as a yellow solid (386 mg). MS (ESI): m/z 302[M+H]⁺.

(g)2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline

The title compound was prepared according to General Procedure A-(d). MS(ESI): m/z 304 [M+H]⁺.

(h) Dihydrochloride salt of2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline

2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline(390 mg, 1.28 mmol) was dissolved in 5 mL of a solution of hydrogenchloride in methanol, stirred for 1 h and concentrated to give thedihydrochloride salt as a pale yellow solid (480 mg). MS (ESI): m/z304[M+H]⁺.

24.2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinoline(Compound 126)

(a) 2,5-Dimethylpyrimidine-4,6-diol

A solution of CH₃ONa (5.02 g, 93 mmol) in CH₃OH (31 mL) was cooled to 0°C. Acetamidine hydrochloride (3.21 g, 34 mmol) was added slowly. Thereaction mixture was stirred at 0° C. for 30 min. Then dimethyl2-methylmalonate (4.5 g, 31 mmol) was added. The mixture was stirred at75° C. for 4 h, during which time a precipitate formed. The solid wasfiltered and dissolved in water and HCl (conc.) was added until pH 1-2.The white precipitate was filtered, and dried in vacuum to give2,5-dimethylpyrimidine-4,6-diol as a white solid (3.41 g). MS (ESI): m/z141 [M+H]⁺.

(b) 4,6-Dichloro-2,5-dimethylpyrimidine

A mixture of 2,5-dimethylpyrimidine-4,6-diol (3.41 g, 24.4 mmol) inPOCl₃ (40 mL) was heated to 100° C. and stirred overnight. After coolingto room temperature, the reaction mixture was poured into water (50 mL)and sodium hydroxide aqueous solution (sat.) was added to the mixtureuntil pII 8-9. The mixture was extracted with EtOAc (150 mL×3). Thecombined organic layers were washed with brine (100 mL), dried overNa₂SO₄, and concentrated under reduced pressure to give crude4,6-dichloro-2,5-dimethylpyrimidine as a yellow solid (2.80 g). MS(ESI): m/z 178 [M+H]⁺.

(c) 6-Chloro-2,5-dimethylpyrimidin-4-amine

A microwave vial was charged with 4,6-dichloro-2,5-dimethylpyrimidinc(523 mg, 2.95 mmol) and ammonium hydroxide (8 mL) in ethanol (4 mL). Thevial was heated to 80° C. and stirred for 8 h. After concentration underreduced pressure, the reaction mixture was extracted with EtOAc (15mL×8). The combined organic layers were washed with brine (30 mL), driedover Na₂SO₄ and concentrated to give6-chloro-2,5-dimethylpyrimidin-4-amine as a yellow solid (411 mg). MS(ESI): m/z 158 [M+H]⁺.

(d) 2,5-Dimethylpyrimidin-4-amine

The title compound was prepared according to General Procedure A-(d). MS(ESI): m/z 124 [M+H]⁺.

(e) 3-Amino-2,5-dimethylpyrimidin-4(3H)-iminium2,4,6-trimethylbenzenesulfonate

The title compound was prepared according to General Procedure N-(d). MS(ESI): m/z 139 [M-199]⁺.

(f) 2-(Chloromethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine

The title compound was prepared according to General Procedure N-(e). MS(ESI): m/z 197 [M+H]⁺.

(g)((5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphoniumchloride

The title compound was prepared according to General Procedure D-(b).The crude product was used in the next step without furtherpurification.

(h)(E/Z)-2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)vinyl)quinoline

The title compound was prepared according to General Procedure D-(c). MS(ESI): m/z 302 [M+H]⁺.

(i)2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinoline

The title compound was prepared according to General Procedure A-(d) MS(ESI): m/z 304 [M+H]⁺.

(j)2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinolinehydrochloride salt

The title compound was prepared according to General Procedure N-(h). MS(ESI): m/z 304 [M+H]⁺.

25. Synthesis of Quinoline and Quinoxaline Derivatives (Compounds127-142)

The procedures outlined above in Examples 23 and 24 for the synthesis of2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinolineand2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinolinewere also carried out with other suitable carbaldehydes, including butnot limited to, substituted quinoline 2-carbaldehydes and substituted orunsubstituted quinoxaline 2-carbaldehydes, which may be commerciallyavailable or prepared using known literature conditions, to prepareother embodiments of the compounds disclosed herein. The synthesis ofexemplary carbaldehydes is described below. The carbaldehydes were thenused as starting material in the preparation of various embodiments ofthe compounds provided herein elsewhere.

(a) 7,8-Difluoro-2-methylquinoline

Sodium 3-nitrobcnzencsulfonatc (2.7 g, 12 mmol) was dissolved in H₂O (3mL), and oleum (4 mL) was added to the mixture. 2,3-Difluoroaniline wasthen added to the mixture. The mixture was heated to 105° C. and(E)-but-2-enal (2.34 g, 33.4 mmol) was added dropwise. The mixture wasstirred at 120° C. for 1 h. Then the mixture was poured into ice (50 g),and solid NaOH was added until pH 12. The mixture was extracted withEtOAc (50 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct was purified by column chromatography to afford7,8-difluoro-2-methylquinoline (1.5 g) as a white solid.

(b) 7,8-Difluoroquinoline-2-carbaldehyde

The title compound was prepared according to General Procedure II-(a).

(c) 2-(Dibromomethyl)benzo[h]quinoline

A mixture of 2-methylbenzo[h]quinoline (0.193 g, 1.0 mmol),1-bromopyrrolidine-2,5-dione (NBS) (600 mg, 3.3 mmol), and AIBN (50 mg,0.3 mmol) in CCl₄(5 mL) was stirred at 80° C. for 4 h. H₂O (20 mL) andDCM (20 mL) were added to the mixture and the layers were separated. Theaqueous layer was extracted with DCM (20 mL×2). The combined organiclayers were washed with brine and dried over anhydrous Na₂SO₄. Theorganic layers were concentrated and purified by column chromatographyto afford 2-(dibromomethyl)benzo[h] quinoline (0.2 g) as a white solid.

(d) Benzo[h]quinoline-2-carbaldehyde

To a mixture of 2-(dibromomethyl)benzo[h]quinoline (52 mg, 0.148 mmol)in EtOH (2 mL) and THF (1 mL) was added a solution of AgNO₃ (75 mg,0.444 mmol) in H₂O (1 mL). The mixture was stirred at reflux for 2 h.The solid was filtered off and the organic solvent was removed underreduced pressure. DCM (5 mL) was added and the layers were separated.The aqueous layer was extracted with DCM (5 mL×2). The combined organiclayers were washed with brine (2 mL) and dried by anhydrous Na₂SO₄. Theorganic layer was concentrated to give benzo[h]quinoline-2-carbaldehyde(30 mg) as a yellow solid.

(e) 2-Methyl-1,8-naphthyridine

To a suspension of 2-aminonicotinaldehyde (732 mg, 6 mmol) and L-proline(69 mg, 0.6 mmol) in EtOH (15 mL) was added acetone (1.74 g, 30 mmol).Then the mixture was heated at reflux and stirred for 8 h. The resultingmixture was concentrated under reduced pressure to give a residue, whichwas washed with water (10 mL) and extracted with DCM (15 mL×3). Thecombined organic layers were washed with brine (10 mL), dried overanhydrous sodium sulfate, and concentrated under reduced pressure toafford the crude product 2-methyl-1,8-naphthyridine as a yellow solid(768 mg). MS (ESI): m/z 145 [M+H]⁺. See e.g., Bioorg. Med. Chem. Lett.,2005, 15, 2679-84.

(f) 1,8-Naphthyridine-2-carbaldehyde

The title compound was prepared according to General Procedure II-(a).MS (ESI): m/z 159 [M+H]⁺.

(g) 2-Methyl-1,5-naphthyridine

A mixture of concentrated sulfuric acid (14 mL), boric acid (1.55 g, 39mmol), sodium m-nitrobenzenesulfonate (11.30 g, 50 mmol), and ironsulfate heptahydrate (0.90 g, 3.23 mmol) was stirred at roomtemperature. Glycerol (8 ml) was added to the mixture followed by3-amino-6-picoline (2.79 g, 25 mmol) and water (14 mL). The mixture washeated at 135° C. for 18 h. The reaction mixture was cooled to roomtemperature, basified using 4 N aqueous sodium hydroxide to pH 8, andextracted with EtOAc (50 mL×3). The organic extracts were combined,concentrated, and the residue was purified by column chromatography toafford 2-methyl-1,5-naphthyridine (2.01 g) as a light brown crystallinesolid. MS (ESI): m/z 145 [M+H]⁺. See, e.g., J. Med. Chem. 2004, 47,4494-4506.

(h) 1,5-Naphthyridine-2-carbaldehyde

The title compound was prepared according to General Procedure H-(a). MS(ESI): m/z 159 [M+H]⁺.

(i) 2,7-Dimethyl-1,8-naphthyridine and 2,6-dimethyl-1,5-naphthyridine

The title compounds were prepared according to J. Org. Chem. 1990, 55,2838-2842.

(j) Ethyl 3-aminoisonicotinate

To an ice-cold suspension of 3-aminoisonicotinic acid (8 g, 58 nmnol) inethanol (36 mL) and toluene (36 mL) was added concentrated sulfuric acid(6.4 mL), and the mixture was stirred for 24 h. The solvents wereremoved under reduced pressure, the residue was dissolved in water, andthe solution was adjusted to pH 8 with concentrated ammonium hydroxideto give ethyl 3-aminoisonicotinate (6.5 g). MS (ESI): m/z 167 [M+H]⁺.

(k) (3-Aminopyridin-4-yl)methanol

The title compound was prepared according to General Procedure 14-(1).MS (ESI): m/z 125 [M+H]⁺.

(l) 3-Aminoisonicotinaldehyde

The title compound was prepared according to General Procedure 14-(m).MS (ESI): m/z 123 [M+H]⁺. See, e.g., Aust. J. Chem., 1993, 46, 987-93.

(m) 2-Methyl-1,7-naphthyridine

The title compound was prepared according to General Procedure 25-(e).MS (ESI): m/z 145 [M+H]⁺.

(n) 1,7-Naphthyridine-2-carbaldehyde

The title compound was prepared according to General Procedure H-(a). MS(ESI): m/z 159 [M+H]⁺.

(o) 2-Methyl-8-nitroquinolin-7-amine

To a solution of 2-methyl-8-nitroquinoline (1.88 g, 10 mmol) and1,1,1-trimethylhydrazinium iodide (3.03 g, 15 mmol) in anhydrousdimethyl sulfoxide (20 mL) was added potassium tert-butoxide as a solid(3.36 g, 30 mmol). The mixture was stirred at room temperature for 1 h.The mixture was then poured into saturated aqueous anmmonium chloride,and extracted with EtOAc. The organic layer was concentrated andpurified by column chromatography to give2-methyl-8-nitroquinolin-7-amine as a yellow solid (300 mg). MS (ESI):m/z 204 (M+H)⁺.

(p) 2-Methylquinoline-7,8-diamine

The title compound was prepared according to General Procedure L-(a). MS(ESI): m/z 174 (M+H)⁺.

(q) 9-Methylpyrido[2,3-f]quinoxaline

To a solution of 2-methylquinoline-7,8-diamine (255 mg, 1.48 mmol) inethanol (3 mL) was added glyoxal (103 mg, 1.78 mmol). The mixture wasstirred at room temperature for 2 h. The mixture was then concentratedto give 9-methylpyrido[2,3-f]quinoxaline as a yellow solid (300 mg). MS(ESI): m/z 196 (M+H)⁺.

(r) Pyrido[2,3-f]quinoxaline-9-carbaldehyde

The title compound was prepared according to General Procedure II-(a).MS (ESI): m/z 210 (M+H)⁺.

(s) 2-Methyl-1,7-phenanthroline

To a mixture of sodium 3-nitrobenzenesulfonate (2.88 g, 12.8 mmol) inoleum (12 mL) and water (12 mL) was added quinolin-5-amine (3.09 g, 21.4mmol). The mixture was stirred and heated to 105° C. Crotonaldehyde(3.00 g, 42.8 mmol) was added dropwise over 15 min. The resultingmixture was stirred at 105 OC for 16 h. The mixture was then poured intoice (50 g), and the pH value was adjusted to 11 with 1 N aqueous sodiumhydroxide solution. The mixture was extracted with EtOAc (3×60 mL), andthe combined organic layers were dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by columnchromatography to afford 2-methyl-1,7-phenanthroline as a yellow solid(2.10 g). MS (ESI) m/z 195.1 (M+H)⁺.

(t) 2-(Dibromomethyl)-1,7-phenanthroline

To a solution of 2-methyl-1,7-phenanthroline (582 mg, 3.0 mmol) intetrachloromethane (20 ml) was added N-bromosuccinimide (2.14 g, 12.0mmol) and 2,2′-azobis(2-methylpropionitrile) (100 mg). The mixture wasstirred at reflux for 5 h. Then saturated sodium bicarbonate aqueoussolution (20 mL) was added. The resulting mixture was extracted with DCM(3×20 mL). The extracts were dried over anhydrous sodium sulfate andconcentrated under reduced pressure to give2-(dibromomethyl)-1,7-phenanthroline as a yellow solid (1.2 g). MS (ESI)m/z 350.9 (M+H)⁺.

(u) 1,7-Phenanthroline-2-carbaldehyde

The title compound was prepared according to General Procedure 25-(d).MS (ESI) m/z 209.0 (M+H)⁺.

26. General Procedure O

(a) 3-Methylquinoxalin-2(1H)-one

A solution of benzene-1,2-diamine (10.8 g, 100 mmol) in ethanol (500 mL)was treated with a solution of ethyl-2-oxopropanoate (11.22 g, 110 mmol)slowly at 0° C., and the resulting suspension was stirred at roomtemperature for 1 h, then filtered. An off-white solid was collected(15.85 g). MS (ESI): mrr/z 161 [M+H]⁺.

(b) 2-Methoxy-3-methylquinoxaline

A suspension of 3-methylquinoxalin-2(1H)-one (3.2 g, 20 mmol), silveroxide (5.56 g, 24 mmol), and methyl iodide (5.68 g, 40 mmol) in toluene(100 mL) was heated to 100° C. for 16 h. After cooling to roomtemperature, the reaction mixture was filtered, concentrated, andpurified by column chromatography to afford the title compound as anorange solid (2.11 g). MS (ESI): m/z 175 [M+H]⁺.

(c)2-(2-(3-Methoxyquinoxalin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-f]quinoline

The title compound was prepared according to General Procedure A-(c).

27. General Procedure P

(a) 2-Nitro-1,4-bis(trifluoromethyl)benzene

1,4-Bis(trifluoromethyl)benzene (10.06 g, 47 mmol) in fuming sulfuricacid (20 g) was cooled to 0° C. Fuming nitric acid (8 g) was addedcautiously. The mixture was heated to 100° C. and stirred for 1 hour. Amixture of fuming nitric acid (6 g) and fuming sulfuric acid (12 g) wasadded, and the mixture was heated to 110° C. and stirred for 6 hours.After cooling to r.t., the mixture was poured into ice water (150 g)cautiously, and extracted with chloroform (100 mL×3). The combinedorganic layers were washed with water (100 mL×2), 10% sodium hydroxideaqueous solution (100 mL×2), and then water (100 mL×2). The resultingorganic layers were dried over sodium sulfate, filtered, andconcentrated to afford 2-nitro-1,4-bis(trifluoromethyl)benzene as an oil(3.3 g).

(b) 2,5-Bis(trifluoromethyl)benzenamine

To a solution of 2-nitro-1,4-bis(trifluoromethyl)benzene (3.3 g, 12.7mmol) in methanol (15 mL) was added a solution of SnCl₂.2H₂O (8.57 g,38.1 mmol) in conc. HCl (15 mL) at room temperature, and the mixture washeated to 50° C. and stirred for 4 hours. Methanol was removed, and theaqueous solution was basified with conc. NaOH solution until pH 10. Thesuspension was diluted with EtOAc (100 mL), and the mixture was stirredat room temperature for 30 minutes and filtered. The solid wasdiscarded, and the filtrate was washed with brine (50 mL), dried oversodium sulfate, and filtered. The solution was concentrated to give2,5-bis(trifluoromethyl)benzenamine as a yellow oil (2.5 g). MS (ESI):m/z 230 [M+H]⁺.

(c) 2-Nitro-3,6-bis(trifluoromethyl)benzenamine

Nitric acid (7 mL) was added to sulfuric acid (10 mL) cautiously at 0°C. 2,5-Bis(trifluoromethyl)benzenamine (2 g, 8.7 mmol) was added insmall portions at 0° C. over 20 minutes and the resulting slurry wasstirred at 0° C. to room temperature for 3 hours. The mixture was pouredinto ice water (100 mL) and basified with sodium hydroxide solution, andextracted with EtOAc (80 mL×3). The combined organic layers were washedwith brine (80 ml), dried over sodium sulfate, filtered and concentratedto give a crude product of 2-nitro-3,6-bis(trifluoromethyl)benzenamine(containing isomers) which was used in the next step without furtherpurification (2.3 g). MS (ESI): m/z 275 [M+H]⁺.

(d) 3,6-Bis(trifluoromethyl)benzene-1,2-diamine

To a solution of 2-nitro-3,6-bis(trifluoromethyl)benzenamine (2.3 g, 8.4mmol) in methanol (10 mL) was added a solution of SnCl₂.2H₂O (7.56 g,33.6 mmol) in concentrated HCl (15 mL). The mixture was heated to 50° C.and stirred for 2 hours. Methanol was removed in vacuum and the aqueoussolution was basified with sodium hydroxide solution. The suspension wasdiluted with EtOAc (150 mL), and the mixture was stirred at roomtemperature for 30 minutes and filtered. The filtrate was washed withbrine (100 mL), dried over sodium sulfate, and filtered. The solutionwas concentrated to give a crude product of 3,6-bis(trifluoromethyl)benzene-1,2-diamine (1.5 g). MS (ESI): m/z 245 [M+H]⁺.

(e) 2-Methyl-5,8-bis(trifluoromethyl)quinoxaline

The title compound was prepared according to General Procedure 25-(q)from 2-oxopropanal, after heating at reflux for 2 h. ¹H-NMR (400 MHz,CDCl₃): δ 8.94 (s, 1H), 8.14 (d, 1H, J=7.6 Hz), 8.10 (d, 1H, J=8.0 Hz),2.87 (s, 3H). MS (ESI): m/z 281 [M+H]⁺.

(f)2-(2-(5,8-Bis(trifluoromethyl)quinoxalin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-f]quinoline

The title compound was prepared according to General Procedure A-(c).

28. General Procedure Q

(a) Pyridine-2,5-diamine

The title compound was prepared according to General Procedure L-(a). MS(ESI): m/z 110.1 [M+H]⁺.

(b) 1,5-Naphthyridin-2-amine

A mixture of pyridine-2,5-diamine (5.2 g, 71% pure, 33.9 mmol), glycerol(15.6 g, 169.5 mmol), sodium 3-nitrobenzenesulphonate (15.2 g, 67.8mmol), sulfuric acid (20 mL), and water (30 mL) was heated to 135° C.and stirred at this temperature for 16 h. The mixture was cooled to roomtemperature and then poured into ice water (150 g). The pH of thereaction mixture was adjusted to 9 with saturated sodium hydroxideaqueous solution. Then the mixture was extracted with EtOAc (3×100 mL).The extracts were dried over sodium sulfate, concentrated under reducepressure to give the crude product. The crude product was purified bycolumn chromatography to give 2.0 g of 1,5-naphthyridin-2-amine as ayellow solid. MS (ESI): m/z 146.1 [M+H]⁺.

(c) 2-Imino-1,5-naphthyridin-1(2H)-amine 2,4,6-trimethylbenzenesulfonate

The title compound was prepared according to General Procedure N-(d). MS(ESI): m/z 161.1 [M+H]⁺.

(d) 2-(Chloromethyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine

The title compound was prepared according to General Procedure N-(e). MS(ESI): m/z 219.0 [M+H]⁺.

(e)(E)-2-(2-(Quinoxalin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine

The title compound was prepared according to General Procedure D-(c). MS(ESI): m/z 325.1 [M+H]⁺.

(f)2-(2-(Quinoxalin-2-yl)ethyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridinehydrochloride salt

To a solution of(E)-2-(2-(quinoxalin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine(32 mg, 0.099 mmol) in 1 N sodium hydroxide aqueous solution (1 mL) andmethanol (2 mL) was added Pd/C (10%, 5 mg). The mixture was stirredunder hydrogen at room temperature for 16 h. The mixture was filteredand the filtrate was concentrated, and purified by reverse phaseprep-HPLC to give 15 mg of2-(2-(quinoxalin-2-yl)ethyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine asa yellow solid.

A solution of2-(2-(quinoxalin-2-yl)ethyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine(15 mg, 0.046 mmol) in 1 N HCl in methanol was stirred at roomtemperature for 10 min. The solvent was removed under reduce pressure togive 18 mg of2-(2-(quinoxalin-2-yl)ethyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridinehydrochloride as a yellow solid. MS (ESI): m/z 327.1 [M+H]⁺.

29. General Procedure R

(a)(E)-2-(2-(Quinolin-2-yl)vinyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridinewas prepared according to General Procedure D-(b) and D-(c). MS (ESI):m/z 324.1 [M+H]⁺. (b)2-(2-(Quinolin-2-yl)ethyl)-[1,2,4]triazolo[1,5-a][1,5]naphthyridine wasprepared according to General Procedure A-(d) and N-(h). MS (ESI): m/z326.1[M+H]⁺.

30. General Procedure S

(a) 2-(Bromomethyl)quinoline was prepared according to General Procedure25-(c) using NBS. MS (ESI): m/z=222.1 [M+H]⁺. (b)Triphenyl(quinolin-2-ylmethyl)phosphonium bromide was prepared accordingto General Procedure D-(b). MS (ESI): m/z=404.1 [M+H]⁺. (c)(E)-2-(2-(Quinolin-2-yl)vinyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridinewas prepared according to General Procedure II-(b). MS (ESI): m/z=324.1[M+H]⁺. (d)2-(2-(Quinolin-2-yl)ethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine wasprepared according to General Procedure Q-(f).

31. General Procedure T

(a) 1,4-Difluoro-2,3-dinitrobenzene The title compound was preparedaccording to General Procedure P-(c). MS (ESI): m/z 205 [M+H]⁺. (b)3,6-Difluorobenzene-1,2-diamine was prepared according to GeneralProcedure L-(a). MS (ESI): m/z 145 [M+H]⁺. (c)5,8-Difluoro-2-methylquinoxaline was prepared according to GeneralProcedure 25-(q) from 2-oxopropanal. MS (ESI): m/z 181 [M+H]⁺. (d)2-(2-(5,8-Difluoroquinoxalin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-f]quinolinewas prepared according to General Procedure A-(c) after heating at 200°C. in a microwave for 3 h.

32. General Procedure U

(a) 1,4-Dichloro-2,3-dinitrobenzene was prepared according to GeneralProcedure P-(c). MS (ESI): m/z 238 [M+H]⁺. (b)3,6-Dichlorobenzene-1,2-diamine was prepared according to GeneralProcedure P-(b). MS (ESI): m/z 178 [M+H]. (c)5,8-Dichloro-2-methylquinoxaline was prepared according to GeneralProcedure 25-(q) from 2-oxopropanal. MS (ESI): m/z 213 [M+H]⁺. (d)2-(2-(5,8-Dichloroquinoxalin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-f]quinolinewas prepared according to General Procedure A-(c) after heating at 200°C. in a microwave for 3 h.

33. General Procedure V

(a)(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)methyl)triphenylphosphoniumchloride was prepared according to General Procedure D-(b). MS (ESI):m/z 423 [M]+. (h)(E)-2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)quinoxalinewas prepared according to General Procedure D-(c). MS (ESI): m/z 303[M+H]⁺. (c)2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoxalinewas prepared according to General Procedure A-(d). See, e.g., Recueildes Travaux Chimiques des Pays-Bas, 1963, (82), 988-995.

34. General Procedure W

(a) 1-Methyl-4-phenyl-1H-imidazole

The title compound was prepared according to General Procedure L-(d). MS(ESI): m/z 159 [M+H]⁺.

(b) 1-Methyl-4-phenyl-1H-imidazole-2-carbaldehyde

The title compound was prepared according to General Procedure 14-(j).MS (ESI): m/z 187 [M+H]⁺.

(c) 2-Bromo-6-(bromomethyl)pyridine

The title compound was prepared according to General Procedure 25-(c)using 1 equivalent of NBS. MS (ESI): m/z 250 [M+H]⁺.

(d) ((6-Bromopyridin-2-yl)methyl)triphenylphosphonium bromide

The title compound was prepared according to General Procedure D-(b).

(e) 2-Bromo-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)-pyridine

The title compound was prepared according to General Procedure D-(c). MS(ESI): m/z 340 [M+H]⁺.

(f) 2-(1H-Imidazol-1-yl)-6-(2-(l-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)pyridine

2-Bromo-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)pyridine (102 mg,0.3 mmol), imidazole (41 mg, 0.6 mmol), CuI (6 mg, 0.03 mmol), and K₂CO₃(124 mg, 0.9 mmol) were mixed in dimethylformamide (2 mL). The resultingsolution was heated for 5 h in a microwave reactor held at a constanttemperature of 160° C. The crude product was purified using reversephase column chromatography to give2-(1H-imidazol-1-yl)-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)-vinyl)pyridine(57 mg). MS (ESI): m/z 328 [M+H]⁺.

(g)2-(1H-Imidazol-1-yl)-6-(2-(l-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)pyridine

The title compound was prepared according to General Procedure A-(d).

35. General Procedure X

(a) 6-(2-(1-Methyl-4-phenyl-1H-imidazol-2-yl)vinyl)-picolinonitrile

To a solution of2-bromo-6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)pyridine (120 mg,0.354 mmol) in dry DMF (3 mL) was added cyanozinc (97 mg, 1.062 mmol)and tetrakis(triphenylphosphine)palladium(0) (41 mg, 0.035 mmol). Themixture was stirred at 130° C. for 3 h in a microwave. The residue wasthen filtered. The filtrate was concentrated and purified by reversephase column chromatography to yield6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)-picolinonitrile (100 mg)as a yellow solid. MS (ESI): m/z 287 [M+H]⁺.

(b) 6-(2-(1-Methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-picolinonitrile

The title compound was prepared according to General Procedure A-(d). MS(ESI): m/z 289 [M+H]⁺.

(c) 6-(2-(1-Methyl-4-phenyl-1H-imidazol-2-yl)ethyl)picolinamide

To a solution of6-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-picolinonitrile (10 mg,0.035 mmol) in dimethyl sulfoxide (2 mL) at 0° C. was added potassiumcarbonate (24 mg, 0.175 mmol) and hydrogen peroxide (12 mg, 0.350 mmol).After stirring at room temperature for 1 h, the mixture was quenchedwith sat. NaHSO₄ (aq.), and extracted with EtOAc (30 mL×2). The organicphase was dried and concentrated under reduced pressure. The residue waspurified by prep-HPLC to give a white solid (3 mg). MS (ESI): m/z 307[M+H]⁺.

The solid was dissolved in 3 mL HCl/MeOH and stirred at r.t for 1 h. Themixture was concentrated under reduced pressure to give a yellow solid(3.3 mg). MS (ESI): m/z 307 [M+H]⁺.

36. General Procedure Y

(a) 6-(2-(1-Methyl-4-phenyl-1H-imidazol-2-yl)vinyl)-2,4′-bipyridine wasprepared according to General Procedure F-(g). MS (ESI): m/z 339 [M+H]⁺.(b) 6-(2-(1-Methyl-4-phenyl-1H-imidazol-2-yl)ethyl)-2,4′-bipyridinehydrochloride salt was prepared according to General Procedure A-(d) andN-(h). MS (ESI): m/z 341 [M+H]⁺.

37. General Procedure Z

(a)(E)-2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5a]pyrazin-2-yl)vinyl)-1,7-phenanthrolineand(E)-9-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)pyrido[2,3-f]quinoxalinewere prepared according to General Procedure D-(c). MS (ESI): m/z 353[M+H]⁺. (b)2-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-1,7-phenanthrolinewas prepared according to General Procedure A-(d). MS (ESI): m/z 355[M+H]⁺. (c)9-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)pyrido[2,3-f]quinoxalinewas prepared according to General Procedures F-(f) and 14-(m).

38. General Procedure AA

(a) 1,7-Naphthyridin-8-amine was prepared according to General ProcedureQ-(b). MS (ESI): m/z 146.1 [M+H]⁺. (b)8-Imino-1,7-naphthyridin-7(8H)-amine 2,4,6-trimethylbenzenesulfonate wasprepared according to General Procedure N-(d). MS (ESI): m/z 161.1[M+H]⁺. (c) 2-(Chloromethyl)-[1,2,4]triazolo[1,5-h][1,7]naphthyridinewas prepared according to General Procedure N-(e). MS (ESI): rm/z 219.0[M+H]⁺. (d)([1,2,4]Triazolo[1,5-h][1,7]naphthyridin-2-ylmethyl)triphenylphosphoniumchloride was prepared according to General Procedure D-(b). MS (ESI):m/z 445 [M]⁺. (e)(E)-2-(2-(Quinolin-2-yl)vinyl)-[1,2,4]triazolo[1,5-h][1,7]naphthyridineand(E)-2-(2-(Quinoxalin-2-yl)vinyl)-[1,2,4]triazolo[1,5-h][1,7]naphthyridinewere prepared according to General Procedure D-(c). MS (ESI): m/z 324.1[M+H]⁺. (f)2-(2-(Quinolin-2-yl)ethyl)-[1,2,4]triazolo[1,5-h][1,7]naphthyridinehydrochloride salt and2-(2-(Quinoxalin-2-yl)ethyl)-[1,2,4]triazolo[1,5-h][1,7]naphthyridinehydrochloride salt were prepared according to General Procedures A-(d)and N-(h).

39. General Procedure BB

(a) 2-(2-(Quinolin-2-yl)ethyl)-3H-imidazo[4,5-h]quinoline and2-(2-(Quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-h]quinoline were preparedaccording to Synthetic Procedure 21 using 6 M HCl and after heating at140° C. in a microwave reactor. MS (ESI): m/z 326 [M+H]⁺. (h)3-Methyl-2-(2-(quinolin-2-yl)ethyl)-3H-imidazo[4,5-h]quinoline and3-methyl-2-(2-(quinoxalin-2-yl)ethyl)-3H-imidazo[4,5-h]quinolinehydrochloride were prepared according to General Procedure L-(d) usingTHF as solvent and General Procedure N-(h).

40. General Procedure CC

(a) Quinoxaline-2-carbaldehyde was prepared according to GeneralProcedure H-(a). MS (ESI): m/z 159.1 [M+H]⁺. (b)2-(2-(Quinoxalin-2-yl)ethyl)-1,10-phenanthroline hydrochloride wasprepared according to General Procedures A-(c) and N-(h).

41. General Procedure DD

(a) 2-(Bromomethyl)quinoline was prepared according to General Procedure25-(c) using 1 equivalent of NBS. MS (ESI): m/z 221 [M+H]⁺. (b)Triphenyl(quinolin-2-ylmethyl)phosphonium bromide was prepared accordingto General Procedure D-(b). MS (ESI): m/z 404 [M]⁺. (c)(E)-2-(2-(Quinolin-2-yl)vinyl)-1,10-phenanthroline was preparedaccording to General Procedure D-(c). MS (ESI): m/z 334.1 [M+H]⁺. (d)2-(2-(Quinolin-2-yl)ethyl)-1,10-phenanthroline hydrochloride wasprepared according to General Procedures F-(f) and N-(h).

42. General Procedure EE

(a) 8-Methoxyquinoline-2-carbaldehyde

The title compound was prepared according to General Procedure H-(a). MS(ESI): m/z 188.1 [M+H]⁺.

(b) (E)-3-(8-Methoxyquinolin-2-yl)acrylic acid

To a suspension of sodium hydride (60%) (0.8 mg, 20.0 mmol) intetrahydrofuran (80 mL) was added methyl 2-(dimethoxyphosphoryl) acetate(2.65 mg, 12 mmol) dropwise at 0° C. After the addition was completed,the mixture was stirred for 30 min at 0° C. A solution of8-methoxyquinoline-2-carbaldehyde (1.87 g, 10.0 mmol) in tetrahydrofuran(20 mL) was then added dropwise over a period of 50 min. The mixture wasstirred at 0° C. for 1 h. A solution of lithium hydroxide hydrate (1.26g, 30.0 mmol) in water (20 mL) was added cautiously to the solution. Theresulting mixture was stirred at room temperature overnight. Thereaction mixture was concentrated under reduced pressure. To the residuewas added water (20 mL), and the pH of the aqueous layer was then adjustto 4 with 1 N hydrogen chloride solution. The precipitate was collectedby filtration and then dried in vacuum to give 1.9 g of the product as awhite solid. MS (ESI): m/z 230.1 [M+H]⁺.

(c) 3-(8-Methoxyquinolin-2-yl)propanoic acid

The title compound was prepared according to General Procedure Q-(f). MS(ESI): m/z 232.1 [M+H]⁺.

(d)2-(2-(8-Methoxyquinolin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-h]quinolineand2-(2-(8-Methoxyquinolin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-f]quinoline

A mixture of 3-(8-methoxyquinolin-2-yl)propanoic acid (116 mg, 0.5 mmol)and methylquinoline-7,8-diamine (260 mg, 1.5 mmol) ormethylquinoline-5,6-diamine (70 mg, 0.4 mmol) was stirred at 160° C. for1 h under nitrogen. After cooling to room temperature, the residue waspurified by column chromatography.

43. General Procedure FF

(a) (8-Methoxyquinolin-2-yl)methanol

The title compound was prepared according to General Procedure 18-(a).MS (ESI): m/z 190.1 [M+H]⁺.

(b) 2-(Chloromethyl)-8-methoxyquinoline

A mixture of (8-methoxyquinolin-2-yl)methanol (1.0 g, 5.3 mmol) andN,N-dimethylformamide (39 mg, 0.53 mmol) in sulfurous dichloride (20 mL)was stirred at room temperature for 2 h. The reaction mixture wasconcentrated and ice water was added. The pH of the aqueous layer wasadjusted to 7 with 10 N sodium hydroxide solution. The mixture wasextracted with DCM (30 mL×3). The combined organic phase was dried withanhydrous sodium sulfate, concentrated, and purified by columnchromatography to give 0.66 g of the product as a yellow solid. MS(ESI): m/z 208.0 [M+H]+.

(c) ((8-Methoxyquinolin-2-yl)methyl)triphenylphosphonium chloride

The title compound was prepared according to General Procedure D-(b). MS(ESI): m/z 434.2 [M]⁺.

(d) (E)-2-(2-(8-Methoxyquinolin-2-yl)vinyl)-1,10-phenanthroline

The title compound was prepared according to General Procedure D-(c). MS(ESI): m/z 364.1 [M+H]⁺.

(e) 2-(2-(8-Methoxyquinolin-2-yl)ethyl)-1,10-phenanthroline

The title compound was prepared according to General Procedure F-(f).

44. General Procedure GG

(a) tert-Butyl pyridin-4-ylcarbamate

To a solution of pyridin-4-amine (2.35 g, 25.0 mmol) in DCM (150 mL) wasadded di-tert-butyl dicarbonate (5.40 g, 25.0 mmol). The mixture wasstirred at room temperature for 2 h. The solvent was removed underreduced pressure. The residue was purified by column chromatography togive 3.6 g of the product as a white solid. MS (ESI): m/z 195.1 [M+H]⁺.

(b) tert-Butyl-3-formylpyridin-4-ylcarbamate

The title compound was prepared according to General Procedure A-(b). MS(ESI): m/z 223.1 [M+H]⁺.

(c) 4-Aminonicotinaldehyde

The title compound was prepared according to General Procedure N-(a). MS(ESI): m/z 123.1 [M+H]⁺.

(d) 2-Methyl-1,6-naphthyridine

The title compound was prepared according to General Procedure 25-(e).MS (ESI): m/z 145.1 [M+H]⁺.

(e) 1,6-Naphthyridine-2-carbaldehyde

The title compound was prepared according to General Procedure H-(a). MS(ESI): m/z 177.1 [M+H]⁺.

(f) (E)-3-(1,6-Naphthyridin-2-yl)acrylic acid

The title compound was prepared according to General Procedure EE-(b).MS (ESI): m/z 201.1 [M+H]+.

(g) 3-(1,6-Naphthyridin-2-yl)propanoic acid

A mixture of (E)-3-(1,6-naphthyridin-2-yl)acrylic acid (300 mg, 1.50mmol) and Pd/C (30 mg, 10%) in 1 N sodium hydroxide aqueous solution (8mL) was stirred under H₂ for 8 h at room temperature, and then filtered.The solution was acidified to pH 4 with 1 N aqueous hydrogen chloridesolution. The precipitate was collected by filtration and dried invacuum to give 220 mg of the product as a yellow solid. MS (ESI): m/z203.1 [M+H]⁺.

(h)2-(2-(1,6-Naphthyridin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-h]quinolinehydrochloride salt

The title compound was prepared according to Synthetic Procedure 21 andGeneral Procedure N-(h). MS (ESI): m/z 340.1 [M+H]⁺.

45. General Procedure HH

(a) 2,5-Dimethylpyridine N-Oxide

A mixture of 2,5-dimethylpyridine (12.5 g, 0.12 mol) and 30% hydrogenperoxide (30 mL) in acetic acid (25 mL) was stirred at 90° C. for 48 h.The reaction mixture was diluted with water (50 mL) and concentrated toa volume of approximately 25 mL. The concentrated solution wasneutralized with solid sodium carbonate, extracted with DCM (100 mL×3),dried with anhydrous sodium sulfate, and concentrated to give 14.4 g ofthe product as a yellow oil. MS (ESI): m/z 124.1 [M+H]⁺.

(b) 2,5-Dimethyl-4-nitropyridine N-Oxide

To 75 mL of concentrated sulfuric acid at 0° C. was added2,5-dimethylpyridine N-oxide (10 g, 0.08 mol) dropwise. 5.6 mL of fumingnitric acid (0.13 mol) was added to the mixture. The mixture was heatedat 90° C. for 6 h, cooled, poured onto 500 mg ice, and neutralized with120 mL of 50% sodium hydroxide solution. The solution was extracted withDCM (250 mL×5), and the combined organic phase was dried with anhydroussodium sulfate and concentrated to give 7.0 g of the crude product as ayellow solid, which was used for the next step without furtherpurification. MS (ESI): m/z 169.1 [M+H]⁺.

(c) 2,5-Dimethylpyridin-4-amine

A mixture of 2,5-dimethyl-4-nitropyridine N-oxide (7.0 g, 41.7 mmol) and10% Pd/C (1.2 g) in acetic acid (60 mL) was stirred under hydrogen at60° C. for 18 h. The solution was cooled, filtered, and diluted withwater (100 mL). The aqueous mixture was neutralized with solid sodiumcarbonate. The solution was extracted with DCM (250 mL×5), and thecombined organic phase was dried with anhydrous sodium sulfate andconcentrated to give 4.6 g of the product as a yellow solid. MS (ESI):m/z 123.1 [M+H]⁺.

(d) 3-Bromo-2,5-dimethylpyridin-4-amine

A mixture of 2,5-dimethylpyridin-4-amine (3.57 g, 29.3 mmol) in 48%hydrogen bromide aqueous solution (40 mL) was heated to 75° C. Then 15%hydrogen peroxide (7 mL) was added dropwise over 30 min. The reactionmixture was stirred at 75° C. for 1 h, and concentrated under reducedpressure. The pH of the solution was adjusted to 9 with 1 N sodiumhydroxide solution. The aqueous mixture was extracted with DCM (250mL×3), and the combined organic phase was washed with saturated sodiumchloride solution (250 mL×1), dried with sodium sulfate, andconcentrated to give 5.0 g of the product as a yellow solid. MS (ESI):m/z 203.1 [M+H]⁺.

(e) (E)-Ethyl 3-(4-amino-2,5-dimethylpyridin-3-yl) acrylate

A mixture of 3-bromo-2,5-dimethylpyridin-4-amine (5.0 g, 25 mmol), ethylacrylate (5.0 g, 50 mmol), diacetoxypalladium (1.12 g, 5.0 mmol), PPh₃(3.28 g, 12.5 mmol), and NEt₃ (7.6 g, 75 mmol) in DMF (50 mL) was heatedin a microwave reactor at 150° C. for 2 h. The reaction mixture wascooled, diluted with water (100 ml), and extracted with DCM (250 mL×3).The combined organic layers were washed with saturated sodium chloridesolution (100 mL×3), dried with sodium sulfate, concentrated, andpurified by column chromatography to give 5.0 g of the product as ayellow solid. MS (ESI): m/z 221.2 [M+H]⁺. (f)5,8-Dimethyl-1,6-naphthyridin-2(1H)-one

A mixture of (E)-ethyl 3-(4-amino-2,5-dimethylpyridin-3-yl) acrylate (5g, 22.7 mmol) and sodium ethanolate (6.2 g, 91 mmol) in ethanol (100 mL)was heated to 80° C. for 2 h. The reaction mixture was concentrated anddiluted with water (50 mL). The aqueous phase was extracted with EtOAc(100 mL×3), and the combined organic layers were washed with saturatedsodium chloride solution, dried with sodium sulfate, and concentrated togive 2.3 g of the product as a yellow solid. MS (ESI): m/z 175.1 [M+H]⁺.

(g) 2-Bromo-5,8-dimethyl-1,6-naphthyridine

A mixture of 5,8-dimethyl-1,6-naphthyridin-2(1H)-one (2.1 g, 12 mmol)and phosphoryl tribromide (5 g) was heated to 110° C. for 1 h, cooled,diluted with ice water, and neutralized with saturated sodiumbicarbonate solution. The aqueous phase was extracted with DCM (100mL×3), and the combined organic layers were dried with sodium sulfateand purified by column chromatography to give 0.63 g of the product as apale white solid. MS (ESI): m/z 237.0 [M+H]+.

(h) (E)-Ethyl 3-(5,8-dimethyl-1,6-naphthyridin-2-yl)acrylate

A mixture of 2-bromo-5,8-dimethyl-1,6-naphthyridine (0.63 g, 2.7 mmol),ethyl acrylate (0.53 g, 5.4 mmol), diacetoxypalladium (121 mg, 0.5mmol), PPh₃ (0.35 g, 1.4 mmol), and NEt₃ (0.82 g, 8.1 mmol) inN,N-dimethylformamide (5 mL) was heated in a microwave reactor at 150°C. for 1 h. The reaction mixture was diluted with water (20 mL) andextracted with EtOAc (50 mL×3). The combined organic layers were washedwith saturated sodium chloride solution (50 mL×3), dried with sodiumsulfate and concentrated to give 0.6 g of the crude product as a yellowsolid, which was used for the next step without further purification. MS(ESI): m/z 257.1 [M+H]⁺.

(i) 3-(5,8-Dimethyl-1,6-naphthyridin-2-yl)propanoic acid

The title compound was prepared according to General Procedure Q-(f). MS(ESI): m/z 231.1 [M+H]⁺.

(j)2-(2-(5,8-Dimethyl-1,6-naphthyridin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-h]quinoline

The title compound was prepared according to General Procedure EE-(d)using polyphosphoric acid after heating at 170° C. for 1 h.

(k)2-(2-(5,8-Dimethyl-1,6-naphthyridin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-f]quinoline

The title compound was prepared according to General Procedure EE-(d)using polyphosphoric acid after heating at 170° C. for 1 h.

(l)2-(2-(5,8-Dimethyl-1,6-naphthyridin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline

The title compound was prepared according to General Procedure EE-(d)using polyphosphoric acid after heating at 170° C. for 1 h.

(m)2-(2-(5,8-Dimethyl-1,6-naphthyridin-2-yl)ethyl)-[1,2,4]triazolo[5,1-t][1,6]naphthyridine

The title compound was prepared according to General Procedure N-(e).

46. General Procedure II

(a) 5-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 2-amino-3-nitrophcnol (15.0 g, 97 mmol) and1,2-dibromoethane (29.1 g, 155 mmol) in dimethylformamide (80 mL) wasadded KOH (10.9 g, 194 mmol) at 180° C. After stirring at 200° C. for 2days, the mixture was poured to 150 g water. The mixture wasconcentrated under reduced pressure. The crude product was purifiedusing column chromatography to give the title compound (2.50 g) as a redsolid. MS (ESI): m/z 181 [M+H]⁺

(b) 3,4-Dihydro-2H-benzo[b][1,4]oxazin-5-amine

The title compound was prepared according to General Procedure L-(a). MS(ESI): m/z 151 [M+H]⁺.

(c) 9-Methyl-2,3-dihydro-1H-[1,4]oxazino[2,3-h]quinoline

The title compound was prepared according to General Procedure 25-(a).MS (ESI): m/z 201 [M+H]⁺.

(d) 1-(9-Methyl-2,3-dihydro-[1,4]oxazino[2,3-h]quinolin-1-yl)ethanone

To a solution of 9-methyl-2,3-dihydro-1H-[1,4]oxazino[2,3-h]quinoline(200 mg, 1.0 mmol) and NEt₃ (304 mg, 3.0 mmol) in DCM (5 mL) was addedacetyl chloride (157 mg, 2.0 mmol) at room temperature. After stirringat room temperature for 1 h, the mixture was washed with water (10mL×3). The organic phase was dried over anhydrous Na₂SO₄ and filtered.The filtrate was concentrated to give the title compound (170 mg) as ayellow solid. MS (ESI): m/z 243 [M+H].

(e) 1-Acetyl-2,3-dihydro-1H-[1,4]oxazino[2,3-h]quinoline-9-carbaldehyde

The title compound was prepared according to General Procedure H-(a). MS(ESI): m/z 257 [M+H]⁺.

(f)(E)-1-(9-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-2,3-dihydro-[1,4]oxazino[2,3-h]quinolin-1-yl)ethanone

The title compound was prepared according to General Procedure D-(c). MS(ESI): m/z 401 [M+H]⁺.

(g)1-(9-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-2,3-dihydro-[1,4]oxazino[2,3-h]quinolin-1-yl)ethanone

The title compound was prepared according to General Procedure A-(d). MS(ESI): m/z 403 [M+H]⁺.

(h)9-(2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-2,3-dihydro-1H-[1,4]oxazino[2,3-h]quinoline

To a solution of1-(9-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-2,3-dihydro-[1,4]oxazino[2,3-h]quinolin-1-yl)ethanone(10 mg, 0.025 mmol) in methanol (1 mL) was added 2 M NaOH (0.05 mL, 0.1mmol) at room temperature. After stirring the mixture at 100° C. for 12h, the solvent was removed. The crude product was purified using reversephase column chromatography (7 mg).

47. General Procedure JJ

(a) 6-Chloro-8-methylquinoline

The title compound was prepared according to General Procedure Q-(b). MS(ESI): m/z 178 [M+H]⁺.

(b) 6-Chloro-8-methyl-5-nitroquinoline

The title compound was prepared according to General Procedure P-(c). MS(ESI): m/z 223 [M+H]+.

(c) N,8-Dimethyl-5-nitroquinolin-6-amine

A mixture of 6-chloro-8-methyl-5-nitroquinoline (420 mg, 1.9 mmol) inmethanamine as a solution in ethyl alcohol (30 mL) was heated to 80° C.and stirred for 1 h. After concentration under reduced pressure, thereaction mixture was extracted with DCM (50 mL). The organic layer waswashed with water (20 mL×2), dried over Na₂SO₄, and concentrated underreduced pressure to give 410 mg of N,8-dimethyl-5-nitroquinolin-6-amineas a yellow solid. MS (ESI): m/z 218 [M+H]⁺.

(d) N⁶,8-Dimethylquinoline-5,6-diamine

The title compound was prepared according to General Procedure L-(a). MS(ESI): m/z 188 [M+H]⁺.

(e) 3,5-Dimethyl-2-(2-(quinolin-2-yl)ethyl)-3H-imidazo[4,5-f]quinolinehydrochloride salt

The title compound was prepared according to Synthetic Procedure 21using a microwave reactor, and General Procedure N-(h). MS (ESI): m/z353 [M+H]⁺.

48. General Procedure KK

(a) 6-Chloro-7-methylquinoline was prepared according to GeneralProcedure Q-(h). MS (ESI): m/z 178 [M+H]⁺. (b)6-Chloro-7-methyl-5-nitroquinoline was prepared according to GeneralProcedure P-(c). MS (ESI): m/z 223 [M+H]+. (c)N,7-Dimethyl-5-nitroquinolin-6-amine was prepared according to GeneralProcedure JJ-(c). MS (ESI): m/z 218 [M+H]⁺. (d)N⁶,7-Dimethylquinoline-5,6-diamine was prepared according to GeneralProcedure L-(a). MS (ESI): m/z 188 [M+H]+. (e)3,4-Dimethyl-2-(2-(quinolin-2-yl)ethyl)-3H-imidazo[4,5-f]quinolinehydrochloride salt was prepared according to Synthetic Procedure 21using a microwave reactor, and General Procedure N-(h). MS (ESI): m/z353 [M+H]+

49. General Procedure LL

(a) Quinolin-8-anine was prepared according to General Procedure L-(a).MS (ESI): m/z 145 [M+H]⁺. (b) 2-Methyl-1,10-phenanthroline was preparedaccording to General Procedure 25-(a). MS (ESI): m/z 195 [M+H]. (c)(E)-2-(2-(3-Methyl-3H-imidazo[4,5-f]quinolin-2-yl)vinyl)-1,10-phenanthrolinewas prepared according to General Procedure A-(c). MS (ESI): m/z 388[M+H]⁺. (d)2-(2-(3-Methyl-3H-imidazo[4,5-f]quinolin-2-yl)ethyl)-1,10-phenanthrolinehydrochloride salt was prepared according to General Procedure F-(f) andN-(h). MS (ESI): m/z 390 [M+H]⁺.

50. General Procedure MM

(a) 2,5-Dimethyl-3-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)vinyl)pyrazine was prepared according to General Procedure A-(c). MS (ESI):m/z 291 [M+H]⁺. (b)2,5-Dimethyl-3-(2-(1-methyl-4-phenyl-1H-imidazol-2-yl)ethyl) pyrazinehydrochloride salt was prepared according to General Procedure Q-(f) andN-(h). MS (ESI): m/z 293.1 [M+H]⁺.

51. General Procedure NN

(a) 1-Methyl-1H-imidazole-2-carbaldehyde

The title compound was prepared according to General Procedure A-(b). MS(ESI): m/z 111.1 [M+H]⁺.

(b) 2-(1,3-Dioxolan-2-yl)-1-methyl-1H-imidazole

A mixture of 1-methyl-1H-imidazole-2-carbaldehyde (24 g, 218 mmol),p-TsOH (16.2 g, 87 mmol), glycol (27 g, 437 mmol), and toluene (700 mL)was heated to 120° C. in a Dean-Stark apparatus for 16 h. Then themixture was cooled to room temperature, pH was adjusted to 9 withsaturated sodium bicarbonate solution at 0 OC, and the mixture wasextracted with EtOAc (500 mL×2). The organic layers were washed withwater (200 mL) and brine (100 mL), dried, filtered, then concentrated togive a red oil (12 g). MS (ESI): m/z 155.1 [M+H]⁺.

(c) 4,5-Dibromo-2-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazole

A mixture of 2-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazole (9 g, 58.4mmol), NBS (20.8 g, 116.8 mmol), 2,2′-azobis(2-methylpropionitrile) (478mg, 2.92 mmol), and chloroform (200 mL) was heated to 62° C. for 16 hunder N₂. Then the mixture was cooled to room temperature, filtered, andconcentrated; and the residue was purified by column chromatography toprovide a light yellow solid (3.6 g). MS (ESI): m/z 313 [M+H]+.

(d) 4-Bromo-2-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazole

To a solution of 4,5-dibromo-2-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazole(1 g, 3.2 mmol) in dry THF (20 mL) was added n-BuLi (2.5 M in hexane,1.28 mL, 3.2 mmol) dropwise at −68° C. over 30 min. The reaction mixturewas stirred at the same temperature for 2 h and then was allowed to warmto r.t. over 1 h. 10 mL of water was added slowly at 0° C. to quench thereaction. The residue was extracted with EtOAc (50 mL×2) and thecombined organic layers were washed with water (20 mL) and brine (20mL), dried, and concentrated to give a yellow oil (678 mg). MS (ESI):m/z 233 [M+H]⁺.

(e) 5-(2-(1,3-Dioxolan-2-yl)-1-methyl-1H-imidazol-4-yl)-2-ethylpyridine

The title compound was prepared according to General Procedure F-(g). MS(ESI): m/z 245 [M+H]⁺.

(l) 1-Methyl-4-(6-methylpyridin-3-yl)-1H-imidazole-2-carbaldehyde

A mixture of5-(2-(1,3-dioxolan-2-yl)-1-methyl-1H-imidazol-4-yl)-2-ethylpyridine (140mg, 0.571 mmol), DCM (5 mL), and 4 N HCl (5 mL) was heated to 45° C. for16 h. Then the mixture was cooled to room temperature, the pH wasadjusted to 6 with saturated sodium bicarbonate solution at 0° C., andthe mixture was concentrated to give a crude product. 30 mL of CH₃CN wasadded and the mixture was filtered. The filtrate was then concentratedto afford a white solid (90 mg). MS (ESI): m/z 202.1 [M+H]⁺.

(g)2-(2-(1-Methyl-4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)ethyl)quinoxalinehydrochloride salt

The title compound was prepared according to General Procedure A-(c) andN-(h). MS (ESI): m/z 293.1 [M+H]⁺.

52. General Procedure AA

(a)(E)-2-(2-(1-Methyl-4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)vinyl)-1,5-naphthyridinewas prepared according to General Procedure A-(c). (b)2-(2-(1-Methyl-4-(6-methylpyridin-3-yl)-1H-imidazol-2-yl)ethyl)-1,5-naphthyridinehydrochloride salt was prepared according to General Procedures A-(d)and N-(h).

53. General Procedure PP

(a) 5,6-Dimethylpyrazine-2-carboxylic acid

To a solution of 2,3-diaminopropanoic acid hydrochloride (1 g, 7.11mmol) in methanol (63 mL) was added sodium hydroxide (1.42 g, 28.4 mmol)at 10° C., and then the mixture was degassed with N₂. After 30 min,biacetyl (612 mg, 7.11 mmol) was added and the reaction mixture wasstirred at the same temperature for 3 h. Dry air was passed through thereaction mixture for 16 h. The solvent was then removed under reducedpressure, the residue was dissolved in water (7 ml), and the solutionwas adjusted to pH 2 with concentrated HCl slowly at 0° C., and themixture was filtered. The yellow solid (580 mg) was used in the nextstep without further purification. MS (ESI): m/z 153.1 [M+H]+.

(b) Methyl 5,6-dimethylpyrazine-2-carboxylate hydrochloride

To a solution of 5,6-dimethylpyrazine-2-carboxylic acid (580 mg, 3.82mmol) in methanol (20 mL) was added thionyl chloride (1.82 g, 15.3 mmol)slowly at 0° C. and the mixture was stirred for 2 h and then heated toreflux for 16 h. The reaction was then cooled to r.t. and concentratedto give the crude product as a yellow solid (700 mg). MS (ESI): m/z167.1 [M+H]⁺.

(c) (5,6-Dimethylpyrazin-2-yl)methanol

To a solution of methyl 5,6-dimethylpyrazine-2-carboxylate hydrochloride(340 mg, 1.68 mmol) in water (10 mL) was added sodium borohydride (320mg, 8.4 mmol) in 5 portions at 0° C. Then the mixture was allowed towarm to room temperature and stirred for 16 h. The solvent was thenremoved under reduced pressure, chloroform (30 mL) was added, themixture was filtered, and the filtrate was concentrated under reducedpressure to give an off yellow solid (125 mg). MS (ESI): m/z 139.1[M+H]⁺.

(d) 5-(Chloromethyl)-2,3-dimethylpyrazine hydrochloride

The title compound was prepared according to General Procedure FF-(b).MS (ESI): m/z 157.1 [M+H]⁺.

(e) ((5,6-Dimethylpyrazin-2-yl)methyl)triphenylphosphonium chloride

The title compound was prepared according to General Procedure D-(b). MS(ESI): m/z 383.1 [M+H]⁺.

(f)2,3-Dimethyl-5-(2-(1-methyl-4-(pyridin-3-yl)-1H-imidazol-2-yl)vinyl)pyrazine

The title compound was prepared according to General Procedure D-(c). MS(ESI): m/z 292.1 [M+H]⁺.

(g)2,3-Dimethyl-5-(2-(1-methyl-4-(pyridin-3-yl)-1H-imidazol-2-yl)ethyl)pyrazine

The title compound was prepared according to General Procedure Q-(f).See, e.g., Chem. Ber., 1967, 100, 555-559.

54. General Procedure QQ

(a) 2-(Chloromethyl)-1,5-naphthyridine and2-(Chloromethyl)-1,8-naphthyridine were prepared according to GeneralProcedure 25-(c) using 1 equivalent of NCS. MS (ESI): m/z 179 [M+H]⁺.(b) ((1,5-Naphthyridin-2-yl)methyl)triphenylphosphonium chloride and((1,8-Naphthyridin-2-yl)methyl)triphenylphosphonium chloride wereprepared according to General Procedure D-(b). MS (ESI): m/z 405[M-Cl]⁺. (c)2-(2-(1,5-Naphthyridin-2-yl)vinyl)-[1,2,4]triazolo[5,1-f]-[1,6]naphthyridineand2-(2-(1,8-naphthyridin-2-yl)vinyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridinewere prepared according to General Procedure D-(c). MS (ESI): m/z 325[M+H]⁺. (d)2-(2-(1,5-Naphthyridin-2-yl)ethyl)-[1,2,4]triazolo[5,1-f]-[1,6]naphthyridineand2-(2-(1,8-naphthyridin-2-yl)ethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridinewere prepared according to General Procedure Q-(f).

55. General Procedure RR

(a) N-Oxide-2-bromopyridine

To a mixture of 2-bromopyridine (4.74 g, 30.0 mmol) in DCM (60 mL) wasadded 3-chlorobenzoperoxoic acid (7.22 g, 42.0 mmol). The mixture wasstirred at room temperature for 16 h. Water (200 mL) was added and themixture was extracted with DCM (200 mL×3). The organic layer wasseparated and dried with anhydrous sodium sulfate. The solution wasconcentrated under reduced pressure. The crude product was purified bycolumn chromatography. The product (5.06 g) was obtained as a whitesolid. MS (ESI): m/z 172, 174 [M+H]+.

(b) N-Oxide-2-bromo-4-nitropyridine

To a solution of N-oxide-2-bromopyridine (5.06 g, 29.6 mmol) in fumingsulfuric acid (100 mL) was added fuming nitric acid (2.84 g, 44.4 mmol)at 0° C. The resulting mixture was heated to 135° C. After stirring for3 hours at this temperature, fuming nitric acid (0.95 g, 14.8 mmol) wasadded and the mixture was stirred for 1 hour. The mixture was cooled toroom temperature and poured into ice water (300 mL). The aqueous layerwas extracted with EtOAc (300 mL×2). The combined organic layers werewashed with sat. sodium bicarbonate (200 mL×5). The organic phase wasconcentrated under reduced pressure, and a brown solid (2.73 g) wasobtained. MS (ESI): m/z 219, 221 [M+H]⁺.

(c) N₂—Benzylpyridine-2,4-diamine

The title compound was prepared according to General Procedure L-(a). MS(ESI): m/z 200 [M+H]⁺.

(d) N-Benzyl-2-methyl-1,6-naphthyridin-5-amine

The title compound was prepared according to General Procedure 25-(a).MS (ESI): m/z 250 [M+H]⁺.

(e) 2-Methyl-1,6-naphthyridin-5-amine

N-Benzyl-2-methyl-1,6-naphthyridin-5-amine (1.42 g, 5.7 mmol) wasdissolved in sulfuric acid (6 mL) and water (3 mL). The solution washeated to 130 OC and stirred for 3 hours. The reaction mixture waspoured into ice water and neutralized with sodium hydroxide adjusting pHto 8-10. The solution was then concentrated under reduced pressure. Thesolid was triturated in ethanol (30 mL×2) and filtered. The filtrate wasconcentrated to dryness and purified by reverse phase columnchromatography, and a brown solid (485 mg) was obtained. MS (ESI): m/z160 [M+H]⁺.

(f) 6-Amino-2-methyl-1,6-naphthyridin-5(6H)-iminium

The title compound was prepared according to General Procedure N-(d-e).MS (ESI): m/z 233 [M+H]⁺.

(g)((8-Methyl-[1,2,4]triazolo[5,1-][1,6]naphthyridin-2-yl)methyl)triphenylphosphoniumchloride

The title compound was prepared according to General Procedure D-(b). MS(ESI): m/z 459 [M+H]⁺.

(h)(E)-2-(2-(1,8-Naphthyridin-2-yl)vinyl)-8-methyl-[1,2,4]triazolo[5,1-f][1,6]naphthyridine

The title compound was prepared according to General Procedure D-(c). MS(ESI): m/z 339 [M+H]+.

(i)2-(2-(1,8-Naphthyridin-2-yl)ethyl)-8-methyl-[1,2,4]triazolo[5,1-f][1,6]naphthyridine

The title compound was prepared according to General Procedure Q-(f).

(j)2-(2-(1,5-Naphthyridin-2-yl)ethyl)-8-methyl-[1,2,4]triazolo[5,1-f][1,6]naphthyridine

The title compound was prepared according to General Procedure D-(c) andQ-(f). See, e.g., J. Mol. Structure, 1997, 415, 53-63.

56. General Procedure SS

(a) 5-Chloro-1,6-naphthyridine

A solution of 1,6-naphthyridin-5(6H)-one (3.2 g, 21.9 mmol) inphosphoryl trichloride (50 mL) was stirred at 100° C. overnight. Thesolvent was removed under vacuum. The residue was cooled to 0° C. Sodiumhydroxide (saturated aqueous solution) was added to adjust the pH to 9.The mixture was extracted with EtOAc (200 mL×3). The combined organiclayers were dried over sodium sulfate and concentrated under vacuum togive 3.3 g of the crude product as a yellow solid. MS (ESI): m/z 165[M+H]⁺.

(b) 5-Azido-1,6-naphthyridine

To a solution of 5-chloro-1,6-naphthyridine (3.3 g, 20.1 mmol) in DMF(40 mL) was added sodium azide (6.0 g, 88.5 mmol). The mixture wasstirred at 80° C. overnight. The mixture was poured into water (120 mL).The aqueous phase was extracted with EtOAc (150 mL×4). The combinedorganic layers were washed with brine (100 mL×3), dried over sodiumsulfate, and concentrated under reduced pressure to give 3.4 g of thecrude product as a brown solid. MS (ESI): m/z 172 [M+H]⁺.

(c) 1,6-Naphthyridin-5-amine

To a suspension of 5-azido-1,6-naphthyridine (3.4 g, 19.9 mmol) inmethanol (40 mL) was added hydrochloric acid (30 mL). Stannous chloridedihydrate (22.5 g, 99.5 mmol) was added. The mixture was stirred at 75°C. for 3.5 h. A yellow precipitate formed. The mixture was filtered togive a yellow solid. The solid was suspended in EtOAc (200 mL). Sodiumhydroxide (saturated aqueous solution) was added to adjust pII to 9. Awhite precipitate formed. The mixture was filtered and the filtrate wasextracted with EtOAc (200 mL×6). The organic phase was dried over sodiumsulfate and concentrated under reduced pressure to give 2.0 g of thecrude product as a yellow solid. MS (ESI): m/z 146 [M+H]⁺.

(d) 6-Amino-1,6-naphthyridin-5(6H)-iminium2,4,6-trimethylbenzenesulfonate

The title compound was prepared according to General Procedure N-(d). MS(ESI): m/z 161 [M+H]⁺.

(e) 2-(Chloromethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine

The title compound was prepared according to General Procedure N-(e). MS(ESI): m/z 219 [M+H]⁺.

(f)([1,2,4]Triazolo[5,1-f][1,6]naphthyridin-2-ylmethyl)triphenylphosphoniumchloride

The title compound was prepared according to General Procedure D-(b). MS(ESI): m/z 445 [M]⁺.

(g)(E)-2-(2-(6-Methyl-1,8-naphthyridin-2-yl)vinyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridine

The title compound was prepared according to General Procedure D-(c). MS(ESI): m/z 339 [M+H]⁺.

(h)2-(2-(6-Methyl-1,8-naphthyridin-2-yl)ethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridinehydrochloride salt

The title compound was prepared according to General Procedures A-(d)and N-(h). MS (ESI): m/z 341 [M+H]⁺.

(i)2-(2-(6-Fluoro-1,8-naphthyridin-2-yl)ethyl)-[1,2,4]triazolo[5,1-f][1,6]naphthyridinehydrochloride salt

The title compound was prepared according to General Procedures D-(c),A-(d), and N-(h). MS (ESI): m/z 345 [M+H]+.

(j)2-(2-(6-(Trifluoromethyl)-1,8-naphthyridin-2-yl)ethyl)-[1,2,4]triazolo[5,1-f][,6]naphthyridinehydrochloride salt

The title compound was prepared according to General Procedures D-(c),A-(d), and N-(h). MS (ESI): m/z 395 [M+H]⁺.

57. General Procedure TT

(a) Ethyl 3-bromo-2-oxobutanoate

To a suspension of CuBr₂ (20.6 g, 92.3 mmol) in EtOAc (500 mL) was addeda solution of ethyl 2-oxobutanoate (4.0 g, 30.7 mmol) in 250 mL ofchloroform. The mixture was heated at reflux for 18 h, cooled, andfiltered through a short pad of silica gel. The solvent was removedunder reduced pressure to give the product as a light green liquid (3.8g).

(b) Methyl 3-methylimidazo[2,1-f][1,6]naphthyridine-2-carboxylate

A solution of 1,6-naphthyridin-5-aminc (700 mg, 4.83 mmol) intctrahydrofuran (25 mL) was added ethyl 3-bromo-2-oxobutanoate (1.51 g,7.24 mmol). The mixture was stirred at reflux for 36 h. Then the mixturewas concentrated under reduced pressure, and purified by columnchromatography to give 740 mg of the product as a yellow solid. MS(ESI): m/z 256.1 [M+H]+.

(c) (3-Methylimidazo[2,1-f][1,6]naphthyridin-2-yl)methanol

A solution of methyl3-methylimidazo[2,1-f][1,6]naphthyridine-2-carboxylate (100 mg, 0.39mmol) in DCM (8 mL) was cooled to 0° C. Diisobutylaluminium hydride (1 Min cyclohexane, 1.2 mL, 1.2 mmol) was added dropwise over 10 min. Thenthe mixture was stirred at 0° C. for 1 h. 2 mL of saturated ammoniumchloride aqueous solution was added slowly to quench the reaction. Then5 ml, of saturated sodium bicarbonate aqueous solution was added. Themixture was extracted with DCM (3×10 mL). The combined organic layerswere dried over sodium sulfate, filtered, and concentrated to give thecrude product. The crude product was purified by column chromatographyto give 42 mg of the product as a yellow solid. MS (ESI) m/z 214.1[M+H]⁺.

(d) 2-(Chloromethyl)-3-methylimidazo[2,1-f][1,6]naphthyridine

The title compound was prepared according to General Procedure FF-(b).MS (ESI): m/z 232.1 [M+H]⁺.

(e)((3-Methylimnidazo[2,1-f][1,6]naphthyridin-2-yl)methyl)triphenylphosphoniumchloride

The title compound was prepared according to General Procedure D-(b). MS(ESI): m/z 458 [M]⁺.

(f)2-(2-(6-Fluoro-1,8-naphthyridin-2-yl)ethyl)-3-methylimidazo[2,1-f][1,6]naphthyridine

The title compound was prepared according to General Procedures D-(c),A-(d), and N-(h). MS (ESI): m/z 358.1 [M+H]⁺.

(g)3-Methyl-2-(2-(6-methyl-1,8-naphthyridin-2-yl)ethyl)imidazo[2,1-f][1,6]naphthyridinehydrochloride salt

The title compound was prepared according to General Procedures A-(d)and N-(h). MS (ESI): m/z 354.1 [M+H]⁺.

(h)3-Methyl-2-(2-(6-(trifluoromethyl)-1,8-naphthyridin-2-yl)ethyl)imidazo[2,1-f][1,6]naphthyridinehydrochloride salt

The title compound was prepared according to General Procedures A-(d)and N-(h). MS (ESI): m/z 408.1 [M+H]⁺. See, e.g., WO2010/126163; J. Org.Chem. 2002, 67, 1102-1108.

58. General Procedure UU

(a) 2,8-Dimethyl-1,5-naphthyridine was prepared according to GeneralProcedure 25-(g). MS (ESI): m/z 159.7 [M+H]⁺. (b)3-Methyl-2-(2-(8-methyl-1,5-naphthyridin-2-yl)ethyl)-3H-imidazo[4,5-f]quinolinehydrochloride salt was prepared according to General Procedures A-(c)and N-(h).

59. General Scheme VV

(a) 3-Methylinidazo[2,1-f][1,6]naphthyridine-2-carbaldehyde was preparedaccording to General Procedure 14-(m). MS (ESI): m/z 212.0 [M+H]⁺. (b)3-Methyl-2-(2-(8-methyl-1,5-naphthyridin-2-yl)vinyl)imidazo[2,1-f][1,6]naphthyridinewas prepared according to General Procedure A-(c). MS (ESI): m/z 352.1[M+H]⁺. (c)3-Methyl-2-(2-(8-methyl-1,5-naphthyridin-2-yl)ethyl)imidazo[2,1-f][1,6]naphthyridinewas prepared according to General Procedures A-(d) and N-(h). ESI MS:m/z 354.1 [M+H]⁺. (d)2-(2-(1,8-Naphthyridin-2-yl)ethyl)imidazo[2,1-a]isoquinoline wasprepared according to General Procedures A-(c), A-(d), and N-(i). ESIMS: m/z 326 [M+H]⁺. (e)2-(2-(7-Methyl-1,8-naphthyridin-2-yl)ethyl)imidazo[2,1-a]isoquinolinewas prepared according to General Procedures A-(c), A-(d), and N-(h).ESI MS: m/z 340 [M+H]⁺. (f)2-(2-(1,8-Naphthyridin-2-yl)ethyl)-3-methylimidazo[2,1-a]isoquinolinewas prepared according to General Procedures A-(c), A-(d), and N-(h).ESI MS: m/z 340 [M+H]⁺. (g)3-Methyl-2-(2-(7-methyl-1,8-naphthyridin-2-yl)ethyl)imidazo[2,1-a]isoquinolinewas prepared according to General Procedures A-(c), A-(d), and N-(h).ESI MS: m/z 354.5 [M+H]⁺. (h)2-(2-(1,5-Naphthyridin-2-yl)ethyl)imidazo[2,1-a]isoquinoline wasprepared according to General Procedures A-(c), A-(d), and N-(h). ESIMS: m/z 326 [M+H]⁺. (i)2-(2-(6-Methyl-1,5-naphthyridin-2-yl)ethyl)imidazo[2,1-a]isoquinolinewas prepared according to General Procedures A-(c), A-(d), and N-(h).ESI MS: m/z 340 [M+H]+. (j)2-(2-(1,5-Naphthyridin-2-yl)ethyl)-3-methylimidazo[2,1-a]isoquinolinewas prepared according to General Procedures A-(c), A-(d), and N-(h).ESI MS: m/z 340 [M+H]⁺. (k)3-Methyl-2-(2-(6-methyl-1,5-naphthyridin-2-yl)ethyl)imidazo[2,1-a]isoquinolinewas prepared according to General Procedures A-(c), A-(d), and N-(h).ESI MS: m/z 354.5 [M+H]⁺.

60. General Procedure WW

2-(2-(Quinoxalin-2-yl)ethyl)-[1,2,4]triazolo[5,1-][1,6]Naphthyridine wasprepared according to General Procedures D-(c) and Q-(f).

61. General Procedure XX

(a) 2-(Chloromethyl)imidazo[2,1-f][1,6]naphthyridine

To a solution of 1,6-naphthyridin-5-amine (145 mg, 1 mmol) in1,2-dimethoxyethane (5 mL) was added 1,3-dichloropropan-2-one (140 mg,1.1 mmol). The solid dissolved immediately and a white precipitate wasobserved. The mixture was stirred at room temperature for 1 h, and thenwas cooled to 0° C. for 20 min. The resulting mixture was filtered togive a white solid. The precipitate was suspended in EtOH (40 mL) andheated at reflux. After refluxing for 2 h, the reaction mixture wasconcentrated under reduced pressure. The residue was dissolved in waterand saturated aqueous NaHCO₃ solution was added to adjust the pH valueto 7. A white suspension formed during the course of addition. Theresulting mixture was stirred for 20 min and then filtered to give2-(chloromethyl)imidazo[2,1-J][1,6]naphthyridine as a white solid (130mg). MS (ESI): m/z 218 [M+H]⁺.

(b) (Imidazo[2,1-f][1,6]naphthyridin-2-ylmethyl)triphenyl phosphoniumchloride

The title compound was prepared according to General Procedure D-(b). MS(ESI): m/z 444 [M-35]+.

(c) 2-(2-(Quinoxalin-2-yl)ethyl)imidazo[2,1-f][1,6]naphthyridine and3-methyl-2-(2-(quinoxalin-2-yl)ethyl)imidazo[2,1-f][1,6]naphthyridine

The title compounds were prepared according to General Procedures D-(c)and Q-(f).

62. General Procedure YY

(a) 3-Chlorohenzene-1,2-diamine was prepared according to GeneralProcedure i-(a). MS (ESI): m/z 143 [M+H]+. (b)8-Chloro-2-methylquinoxaline and 5-chloro-2-methyl quinoxaline wasprepared according to General Procedure 25-(p). MS (ESI): m/z 179 [M+H].(c)2-(2-(8-Chloroquinoxalin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-f]quinolinewas prepared according to General Procedure A-(d).

63. General Procedure ZZ

(a) 2,3-Dimethyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinoline A mixtureof 2,3-dimethyl-3H-imidazo[4,5-f]quinoline (0.40 g, 2.03 mmol) andplatinum (IV) oxide (24 mg, 0.11 mmol) in HCl (6 N, 2 mL) and ethanol(10 mL) was stirred at room temperature under H₂ for 24 h. Then ethanolwas removed under reduced pressure and the residue was dissolved inEtOAc (20 mL) and sat. NaHCO₃ (3 mL), filtered through Celite, washedwith EtOAc (10 mL×3), and separated. The water layer was then extractedwith EtOAc (10 mL×3). The combined organic layers were dried with Na₂SO₄and filtered; and the solvent was removed under reduced pressure to givea yellow solid. The residue was used in the next step without furtherpurification (320 mg). MS (ESI): m/z 202 [M+H]⁺.

(b) Benzyl2,3-dimethyl-8,9-dihydro-3H-imidazo[4,5-f]quinoline-6(7H)-carboxylate

A solution of 2,3-dimethyl-6,7,8,9-tetrahydro-3H-imidazo[4,5-J]quinoline(400 mg, 2 mmol) in tetrahydrofuran (10 mL) was stirred at 0° C. ThenNaOH (1 N, 10 mL, 10 mmol) was added to the solution and the mixture wasstirred at 0° C. for 10 minutes. Phenyl carbonochloridate (1.02 g, 6mmol) was then added and the mixture was stirred at 0° C. for 1 hour.The layers were then separated and the water layer was extracted withEtOAc (10 mL×3). The combined organic layers were dried with Na₂SO₄ andfiltered; and the solvent was removed under reduced pressure. Theresidue was purified with prep-TLC to give the product as a yellow oil(0.53 g). MS (ESI): m/z 336 [M+H]+.

(c) Benzyl2-formyl-3-methyl-8,9-dihydro-3H-imidazo[4,5-f]quinoline-6(7H)-carboxylate

The title compound was prepared according to General Procedure H-(a). MS(ESI): m/z 350 [M+H]⁺.

(d)3-Methyl-2-(2-(quinoxalin-2-yl)ethyl)-6,7,8,9-tetrahydro-3H-imidazo[4,5-f]quinoline

The title compound was prepared according to General Procedures D-(c)and Q-(f).

64. General Procedure AAA

(a) Methyl 3-iodopropanoate

To a solution of methyl 3-bromopropanoate (20 g, 0.12 mol) in acetone(40 mL) was added sodium iodide (23.4 g, 0.156 mol), and the resultingmixture was heated to 55° C. for 16 h. The mixture was then filtered,the filter cake was rinsed with ethyl ether (50 mL), and the filtratewas concentrated under reduced pressure. The residue was dissolved inethyl ether (100 mL) and washed with ice water (2×50 mL), brine (30 mL),dried over anhydrous sodium sulfate, and filtered; and the solution wasconcentrated to provide a red oil (11 g).

(b) Methyl-3-(4,6-dimethylpyrimidin-2-yl)propanoate

A suspension of Zn—Cu couple (3.45 g) in toluene/N,N-dimethylacetamide(14:1, 30 mL) was degassed by bubbling N₂ through the suspension for 15min. Then methyl 3-iodopropanoate (1.96 g, 9.14 mmol) was added to thesuspension, and the resulting mixture was heated at 110° C. for 6 h. Thereaction mixture was allowed to cool to 70° C., and2-chloro-4,6-dimethylpyrimidine (961 mg, 6.77 mmol) andtetrakis(triphenylphosphine) palladium (235 mg, 0.203 mmol) were added.The reaction mixture was maintained at 70° C. for 22 h. Upon cooling tor.t., the mixture was filtered, and the filter cake was rinsed withether (10 mL×3). The filtrate was extracted with 1 M hydrochloric acid(75 mL×2). The acidic extracts were basified with the addition of sodiumbicarbonate, and the resulting solution was extracted with ether (75mL×2). The combined organic layers were dried over anhydrous sodiumsulfate and the solution was concentrated to give a residue, which waspurified by prep-TLC to afford methyl 3-(4,6-dimethylpyrimidin-2-yl)propanoate as a pale-yellow solid (120 mg). MS (ESI): m/z195 [M+H]⁺.

(c)2-(2-(4,6-Dimethylpyrimidin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-f]quinoline

The title compound was prepared according to Synthetic Procedure 21.

(d)3-Methyl-2-(2-(4-methylquinazolin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline

The title compound was prepared according to Generic Procedure AAA(a-c).

(e)3-Methyl-2-(2-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)ethyl)-3H-imidazo[4,5-f]quinoline

The title compound was prepared according to Generic Procedure AAA(a-c).

65. General Procedure BBB

(a) Methyl 4-ethoxy-4-iminobutanoate

A solution of methyl 3-cyanopropanoate (1.5 g, 13.3 mmol) and ethanol(0.61 g, 13.3 mmol) in n-hexane (15 mL) was cooled to −30° C., andanhydrous hydrogen chloride was bubbled into the solution for 1 h. Themixture was allowed to stand overnight at about −15° C., then at 5-10°C. for 16 h. The solvent was decanted, and the residue was diluted withdiethyl ether (30 mL×2) and a solution of K₂CO₃ (3.67 g, 26.6 mmol) inwater (25 mL), the organic layer was washed with water (20 mL) and brine(10 mL), dried, and concentrated to give a colorless oil (1.34 g). MS(ESI): m/z 160 [M+H]⁺.

(b) Methyl 4-ethoxy-4-iminobutanoate

To a solution of methyl 4-ethoxy-4-iminobutanoate (1.34 g, 8.4 mmol) inethanol (25 mL) was added ammonium chloride (450 mg, 8.4 mmol), and thereaction mixture was heated at reflux for 16 h. The reaction was thencooled to room temperature and filtered, and the filtrate wasconcentrated to provide methyl 4-amino-4-iminobutanoate hydrochloride (1g) as a white solid. MS (ESI): m/z 131 [M+H]⁺.

(c) Ethyl3-(4,6-dihydroxy-4,6-bis(trifluoromethyl)-1,4,5,6-tetrahydropyrimidin-2-yl)propanoate

To a solution of methyl 4-ethoxy-4-iminobutanoate (800 mg, 4.8 mmol) and1,1,1,5,5,5-hexafluoropentane-2,4-dione (1.2 g, 4.8 mmol) in ethanol (40mL) was added concentrated H₂SO₄ (2 drops). Then the resulting mixturewas heated at reflux for 16 h. The reaction was then cooled to roomtemperature, and the mixture was neutralized with saturated sodiumcarbonate solution to pH 7, and then extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate, and concentrated under reduced pressure toprovide a white solid as the crude product (400 mg), which was used inthe next step without purification. MS (ESI): m/z 353.1 [M+H]⁺.

(d) Ethyl 3-(4,6-bis(trifluoromethyl)pyrimidin-2-yl)propanoate

A mixture of ethyl3-(4,6-dihydroxy-4,6-bis(trifluoromethyl)-1,4,5,6-tetrahydro-pyrimidin-2-yl)propanoate(400 mg, 1.14 mmol), p-toluenesulfonic acid (210 mg, 1.14 mmol), andtoluene was heated to 110° C. for 2 h. The reaction was then cooled toroom temperature, the mixture was neutralized with saturated sodiumcarbonate solution to pH 7 and then extracted with EtOAc (50 mL×3). Thecombined organic layers were washed with brine (30 mL), dried overanhydrous sodium sulfate, and concentrated under reduced pressure; andthe residue was purified by prep-TLC to give the title compound (100mg). MS (ESI): m/z 317 [M+H]⁺

(e)2-(2-(4,6-bis(Trifluoromethyl)pyrimidin-2-yl)ethyl)-3-methyl-3H-imidazo[4,5-f]quinoline

The title compound was prepared according to General Procedure 21. See,e.g., Chem. Commun., 2009, 2145-2147.

B. Compounds

The following compounds were prepared using the above procedures.

Compound Method of No. Structure Preparation Analytical Data  1

A LC-MS: m/z 301.4 (M + H⁺); ¹H NMR (CDCl₃): δ 8.80 (s, 1H), 8.14-8.08(m, 2H), 7.84-7.65 (m, 3H), 7.40-7.35 (t, J = 7.6 Hz, 3H), 7.24-7.23 (m,2H), 3.55-3.41 (m, 4H).  2

A LC-MS: m/z 317.1 (M + H⁺); ¹H NMR (CD₃OD): δ 7.81 (d, J = 7.9 Hz, 1H),7.65 (d, J = 7.7 Hz, 2H), 7.54-7.49 (m, 1H), 7.38-7.19 (m, 6H),3.36-3.32 (m, 2H), 3.28-3.25 (m, 2H).  3

A MS (ESI) m/z 317.4 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 11.93 (s,1H), 12.56 (s, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.80-7.74 (m, 3H), 7.61(d, J = 8.0 Hz, 1H), 7.47 (m, 2H), 7.32 (m, 2H), 7.16 (m, 1H), 3.17-3.14(m, 2H), 3.10-3.07 (m, 2H).  4

A MS (ESI) m/z 318.4 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 15.24 (brs,1H), 14.63 (brs, 1H), 9.04 (s, 1H), 8.66 (d, J = 5.2 Hz, 1H), 8.04 (q, J= 5.2 Hz, 2H), 7.91 (d, J = 7.6 Hz, 2H), 7.51 (m, 2H), 7.44 (m, 1H),3.51 (q, J = 6.8 Hz, 2H), 3.37 (q, J = 6.6 Hz, 2H).  5

A MS (ESI) m/z 318.4 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 9.25 (s,1H), 8.78 (d, J = 5.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 2H), 7.51 (dd, ¹J =4.8 Hz, ²J = 0.4 Hz, 1H), 7.45 (brs, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.16(t, J = 7.6 Hz, 1H), 3.12-3.17 (m, 4H).  6

A MS (ESI) m/z 367.4 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 12.4 (s,1H), 11.97 (s, 1H), 8.81 (s, 1H), 8.19 (d, J = 8.8 Hz, 2H), 8.08 (d, J =8.8 Hz, 1H), 7.78 (s, 2H), 7.65 (t, 1H), 7.58 (t, 1H), 7.50 (s, 1H),7.33 (m, 2H), 7.15 (m, 1H), 3.20 (m, 2H), 3.12 (m, 2H).  7

A MS (ESI) m/z 377.41 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.85 (d, J =1.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.37 (s, 1H), 7.30-7.34 (m, 2H),7.14 (q, J = 4.3 Hz, 1H), 6.84 (s, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 3.02(q, J = 3.8 Hz, 2H), 2.84 (q, J = 3.8 Hz, 2H).  8

A LC-MS: m/z 331.4 (M + H⁺); ¹H NMR (CDCl₃): δ 13.79 (s, 1H), 8.32-8.29(dd, ¹J = 7.9 Hz, ²J = 1.1 Hz, 1H), 7.93-7.90 (m, 2H), 7.77-7.66 (m,2H), 7.49-7.43 (t, J = 7.7 Hz, 3H), 7.31- 7.26 (t, J = 7.4 Hz, 1H), 7.14(s, 1H), 3.64 (s, 3H), 3.37-3.33 (m, 2H), 3.17- 3.13 (m, 2H).  9

A LC-MS: m/z 329.4 (M + H⁺); ¹H NMR (CDCl₃): δ 8.32-8.29 (d, J = 7.9 Hz,1H), 7.91-7.86 (m, 2H), 7.78-7.67 (m, 3H), 7.49-7.42 (m, 4H), 7.35-7.33(m, 2H), 3.82 (s, 3H).  10

A LC-MS: m/z 331.4 (M + H⁺); ¹H NMR (CD₃OD): δ. 8.22-8.19 (dd, ¹J = 8.0Hz, ²J = 1.2 Hz, 1H), 7.79-7.76 (m, 1H), 7.70-7.64 (m, 3H), 7.53-7.47(t, J = 8.1 Hz, 1H), 7.38-7.33 (t, J = 7.6 Hz, 2H), 7.29 (s, 1H),7.25-7.22 (m, 1H), 3.67 (s, 3H), 3.37 (s, 4H).  11

A LC-MS: m/z 300.4 (M + H⁺); ¹H NMR (CDCl₃): δ. 11.30 (s, 1H), 8.16-8.14(m, 2H), 7.86 (d, J = 8.2 Hz, 1H), 7.79 (t, J = 7.0 Hz, 2H), 7.62-7.55(m, 2H), 7.41-7.35 (m, 3H), 7.24-7.21 (m, 2H), 3.50-3.44 (m, 4H).  12

A LC-MS: m/z 299.3 (M + H⁺); ¹H NMR (CDCl₃): δ. 12.80 (s, 1H), 13.05 (s,1H), 8.14 (d, J = 8.0 Hz, 1H), 8.03- 7.86 (m, 6H), 7.74 (m, 1H), 7.52(d, J = 16.3 Hz, 1H), 7.39 (s, 1H), 7.24 (s, 1H).  13

A LC-MS: m/z 301.3 (M + H⁺); ¹H NMR (CDCl₃): δ. 9.44 (s, 1H), 8.08-7.97(m, 3H), 7.72-7.67 (m, 3H), 7.38 (t, J = 7.5 Hz, 2H), 7.25-7.21 (m, 2H),3.67- 3.63 (m, 2H), 3.50-3.46 (m, 2H).  14

A LC-MS: m/z 317 (M + H⁺); ¹H NMR (CD₃OD): δ 8.20 (dd, ¹J = 7.6 Hz, ²J =1.1 Hz, 1H), 7.83-7.79 (m, 1H), 7.69 (d, J = 8.3 Hz, 3H), 7.54-7.51 (m,1H), 7.42-7.29 (m, 3H), 6.50 (s, 1H), 3.22- 3.20 (m, 2H), 3.10-3.08 (m,2H).  15

A LC-MS: m/z 331 (M + H⁺); ¹H NMR (CD₃OD): δ 8.21 (d, J = 7.9 Hz, 1H),7.86-7.81 (m, 1H), 7.70 (d, J = 7.1 Hz, 3H), 7.52 (t, J = 7.6 Hz, 1H),7.39- 7.26 (m, 3H), 6.50 (s, 1H), 3.91 (s, 3H), 3.28-3.23 (m, 2H),3.13-3.08 (m, 2H).  16

A LC-MS: m/z 302.4 (M + H⁺); ¹H NMR (CD₃OD): δ 9.12 (dd, ¹J = 4.3 Hz, ²J= 1.8 Hz, 1H), 8.91 (s, 1H), 8.57 (dd, ¹J = 8.4 Hz, ²J = 1.7 Hz, 1H),7.85 (dd, ¹J = 8.4 Hz, ²J = 4.3 Hz, 1H), 7.63 (d, J = 7.5 Hz, 2H),7.37-7.32 (t, J = 7.6 Hz, 2H), 7.26-7.19 (m, 2H), 3.63-3.58 (m, 2H),3.43-3.38 (m, 2H).  17

A LC-MS: m/z 302.4 (M + H⁺).  18

A LC-MS: m/z 315 (M + H⁺); ¹H NMR (CDCl₃): δ 9.35 (s, 1H), 7.97 (d, J =8.1 Hz, 1H), 7.91-7.87 (m, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.63-7.59 (m,1H), 7.34-7.31 (m, 2H), 7.21-7.17 (m, 1H), 7.07 (d, J = 1.1 Hz, 1H),3.71-3.66 (m, 5H), 3.42-3.38 (m, 2H).  19

A LC-MS: m/z 314 (M + H⁺); ¹H NMR (CDCl₃): δ 8.05 (d, J = 8.4 Hz, 1H),8.01 (d, J = 8.4 Hz, 1H), 7.77-7.73 (m, 3H), 7.70-7.66 (m, 1H),7.50-7.46 (m, 1H), 7.37-7.33 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H),7.25-7.18 (m, 1H), 6.98 (s, 1H), 3.52-3.48 (m, 2H), 3.46 (s, 3H),3.30-3.26 (m, 2H); ¹³C NMR (CDCl₃): 161.4, 148.3, 148.1, 140.2, 136.4,134.7, 129.5, 128.9, 128.7, 127.8, 127.0, 126.5, 126.0, 124.9, 122.1,116.4, 37.48, 32.86, 26.34.  20

A LC-MS: m/z 315 (M + H⁺); ¹H NMR (CDCl₃): δ 8.82 (s, 1H), 8.08-8.02 (m,2H), 7.75-7.69 (m, 4H), 7.36-7.32 (m, 2H), 7.22-7.20 (m, 1H), 7.02 (s,1H), 3.75-3.57 (m, 2H), 3.55 (s, 3H), 3.31- 3.28 (m, 2H).  21

B LC-MS: m/z 291.1 (M + H⁺); ¹H NMR (DMSO-d₆): δ 12.36 (s, 1H), 12.28(s, 1H), 8.09 (dd, ¹J = 7.8 Hz, ²J = 1.1 Hz, 1H), 7.80-7.74 (m, 1H),7.58 (d, J = 8.0 Hz, 1H), 7.49-7.36 (m, 3H), 7.11 (d, J = 5.3 Hz, 2H),3.41-3.36 (m, 2H), 3.21-3.16 (m, 2H).  22

B LC-MS: m/z 289.1 (M + H⁺); ¹H NMR (DMSO-d₆): δ 12.95 (s, 1H), 12.60(s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 16.1 Hz, 1H), 7.87-7.81(m, 1H), 7.73-7.62 (m, 2H), 7.55-7.50 (m, 2H), 7.44 (d, J = 16.1 Hz,1H), 7.25 (s, 2H).  23

B LC-MS: m/z 303.2 (M + H⁺); ¹H NMR (DMSO-d₆): δ 12.55 (s, 1H), 8.16-8.08 (m, 2H), 7.87-7.82 (m, 1H), 7.75- 7.68 (m, 2H), 7.66 (dd, ¹J = 11.9Hz, ²J = 1.5 Hz, 1H), 7.57-7.50 (m, 2H), 7.34-7.24 (m, 2H), 3.98 (s,3H).  24

B LC-MS: m/z 305.1 (M + H⁺); ¹H NMR (DMSO-d₆): δ 12.34 (s, 1H), 8.08 (d,J = 7.4 Hz, 1H), 7.79-7.74 (m, 1H), 7.60-7.43 (m, 4H), 7.21-7.11 (m,2H), 3.81 (s, 3H), 3.45-3.39 (m, 2H), 3.25- 3.20 (m, 2H).  25

B LC-MS: m/z 288 (M + H⁺); ¹H NMR (CDCl₃): δ 8.05-8.03 (m, 2H), 7.79-7.68 (m, 3H), 7.50 (t, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.28-7.23 (m, 3H),3.71 (s, 3H), 3.66-3.62 (m, 2H), 3.52-3.47 (m, 2H).  26

B LC-MS: m/z 289 (M + H⁺); ¹H NMR (CDCl₃): δ 8.82 (s, 1H), 8.06-8.00 (m,2H), 7.73-7.68 (m, 3H), 7.26-7.21 (m, 3H), 3.74 (s, 3H), 3.72-3.69 (m,2H), 3.50-3.46 (m, 2H).  27

C LC-MS: m/z 317 (M + H⁺); ¹H NMR (DMSO-d₆): δ 12.27 (s, 1H), 8.08 (d, J= 7.4 Hz, 1H), 7.82-7.64 (m, 6H), 7.49 (t, J = 14.7 Hz, 1H), 7.35-7.30(t, J = 7.4 Hz, 1H), 7.19-7.14 (m, 1H), 4.49- 4.45 (t, J = 6.8 Hz, 2H),3.17-3.12 (t, J = 13.5 Hz, 2H).  28

D LC-MS: m/z 253.3 (M + H⁺); ¹H NMR (CDCl₃): δ 7.72 (d, J = 7.3 Hz, 2H),7.49 (d, J = 16.1 Hz, 1H), 7.42-7.34 (m, 3H), 7.30-7.25 (m, 1H), 7.19(d, J = 5.0 Hz, 1H), 7.02-7.01 (m, 1H), 6.80-6.93 (m, 1H), 6.80 (d, J =16.1 Hz, 1H).  29

D LC-MS: m/z 255.3 (M + H⁺); ¹H NMR (CDCl₃): δ 7.68-7.65 (m, 2H), 7.36(t, J = 7.6 Hz, 2H), 7.25-7.17 (m, 3H), 6.89 (dd, ¹J = 5.1 Hz, ²J = 3.5Hz, 1H), 6.83 (d, J = 3.2 Hz, 1H), 3.33- 3.27 (m, 2H), 3.11-3.06 (m,2H).  30

D LC-MS: m/z 247.3 (M + H⁺); ¹H NMR (CD₃OD): δ 7.75 (d, J = 7.8 Hz, 2H),7.60-7.57 (m, 2H), 7.45-7.37 (m, 6H), 7.31 (dd, ¹J = 12.3 Hz, ²J = 7.2Hz, 2H), 7.06 (d, J = 16.6 Hz, 1H).  31

D LC-MS: m/z 249.3 (M + H⁺); ¹H NMR (CD₃OD): δ 7.82-7.75 (m, 3H), 7.67-7.64 (m, 3H), 7.47-7.33 (m, 4H), 7.27- 7.20 (m, 1H), 3.26-3.21 (m, 2H),3.16- 3.10 (m, 2H).  32

D LC-MS: m/z 248.3 (M + H⁺); ¹H NMR (CD₃OD): δ 8.60 (dd, ¹J = 4.9 Hz, ²J= 0.8 Hz, 1H), 7.88-7.84 (m, 1H), 7.79- 7.76 (m, 2H), 7.64-7.61 (m, 2H),7.53 (s, 2H), 7.48-7.43 (t, J = 7.5 Hz, 2H), 7.38-7.34 (m, 2H).  33

D LC-MS: m/z 250.3 (M + H⁺); ¹H NMR (CD₃OD): δ. 8.50-8.47 (m, 1H), 7.77-7.71 (m, 1H), 7.65 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 1.6 Hz, 2H),7.29-7.19 (m, 4H), 3.27-3.21 (m, 2H), 3.17-3.12 (m, 2H).  34

D LC-MS: m/z 316.3 (M + H⁺); ¹H NMR (DMSO-d₆ + D₂O): δ 8.11 (d, J = 8.1Hz, 1H), 7.87 (s, 1H), 7.68-7.62 (m, 3H), 7.52-7.38 (m, 5H), 6.31 (s,1H), 3.30 (t, J = 7.2 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H).  35

D LC-MS: m/z 299.1 (M + H⁺); ¹H NMR (DMSO-d₆): δ 7.87-7.82 (m, 3H),7.75-7.70 (m, 3H), 7.50 (m, 4H), 7.32 (t, J = 7.4 Hz, 2H), 7.18-7.13 (m,1H), 3.22-3.16 (m, 2H), 3.06-3.01 (m, 2H).  36

D LC-MS: m/z 300.1 (M + H⁺); ¹H NMR (CD₃OD): δ. 9.23 (s, 1H), 8.08 (d, J= 8.6 Hz, 1H), 7.86-7.83 (m, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.66-7.61(m, 4H), 7.38-7.33 (t, J = 7.6 Hz, 2H), 7.25- 7.22 (m, 2H), 3.41-3.35(m, 2H), 3.26- 3.21 (m, 2H).  37

E LC-MS: m/z 333 (M + H⁺); ¹H NMR (DMSO-d₆) δ. 12.25 (s, 1H), 8.09. (dd,¹J = 7.9 Hz, ²J = 1.3 Hz, 1H), 7.82- 7.76 (m, 1H), 7.63 (d, J = 7.8 Hz,1H), 7.57-7.54 (m, 2H), 7.50-7.45 (t, J = 8.0 Hz, 1H), 7.38 (t, J = 7.5Hz, 2H), 7.31-7.23 (m, 2H), 6.92 (d, J = 3.6 Hz, 1H), 3.32-3.29 (m, 2H),3.02-2.99 (m, 2H).  38

E LC-MS: m/z 331 (M + H⁺); ¹H NMR (DMSO-d₆): δ. 12.31 (s, 1H), 8.14 (d,J = 7.2 Hz, 1H), 7.96-7.88 (m, 2H), 7.76-7.72 (m, 2H), 7.67-7.45 (m,5H), 7.39-7.34 (m, 1H), 7.26 (d, J = 12.6 Hz, 1H), 6.16 (d, J = 12.5 Hz,1H).  39

F LC-MS: m/z 304.4 (M + H⁺); ¹H NMR (DMSO-d₆ + D₂O): δ 8.25 (d, J = 8.6Hz, 1H), 7.94 (t, J = 8.3 Hz, 2H), 7.73 (t, J = 5.3 Hz, 1H), 7.52-7.44(m, 3H), 7.25 (s, 1H), 6.48-6.46 (m, 2H), 3.53 (s, 3H), 3.36-3.31 (m,2H), 3.16-3.11 (m, 2H).  40

F LC-MS: m/z 320.4 (M + H⁺); ¹H NMR (DMSO-d₆ + D₂O): δ 8.25 (d, J = 8.5Hz, 1H), 7.94 (dd, ¹J = 12.0 Hz, ²J = 8.5 Hz, 2H), 7.73 (t, J = 7.7 Hz,1H), 7.56-7.51 (m, 2H), 7.47-7.44 (m, 2H), 7.34 (d, J = 4.9 Hz, 1H),7.27 (s, 1H), 3.53 (s, 3H), 3.53-3.30 (m, 2H), 3.17- 3.12 (m, 2H).  41

F LC-MS: m/z 315.4 (M + H⁺); ¹H NMR (CDCl₃): δ 8.57-8.55 (m, 2H), 8.09-8.04 (m, 2H), 7.81 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 8.4 Hz, 1H),7.63-7.61 (m, 2H), 7.55-7.50 (m, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.22 (s,1H), 3.58 (s, 3H), 3.56-3.51 (m, 2H), 3.35-3.30 (m, 2H).  42

F LC-MS: m/z 332.4 (M + H⁺); ¹H NMR (CDCl₃): δ 8.20-8.14 (m, 1H), 8.05(d, J = 8.3 Hz, 2H), 7.80 (d, J = 8.2 Hz, 1H), 7.74-7.69 (m, 1H), 7.52(t, J = 15.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.22-7.14 (m, 3H),7.11-7.04 (m, 1H), 3.56-3.51 (m, 5H), 3.34-3.29 (m, 2H).  43

F LC-MS: m/z 332.4 (M + H⁺); ¹H NMR (CDCl₃): δ 8.05 (d, J = 8.3 Hz, 2H),7.80 (d, J = 8.0 Hz, 1H), 7.74-7.68 (t, J = 8.3 Hz, 1H), 7.51-7.44 (m,3H), 7.34-7.29 (m, 2H), 7.04 (s, 1H), 6.90 (t, J = 8.4 Hz, 1H),3.55-3.50 (m, 5H), 3.33-3.28 (m, 2H).  44

F LC-MS: m/z 350.2 (M + H⁺); ¹H NMR (DMSO-d₆): δ. 8.47 (d, J = 8.5 Hz,1H), 8.01 (d, J = 8.0 Hz, 1H), 7.95- 7.90 (m, 2H), 7.81 (t, J = 15.0 Hz,1H), 7.65-7.59 (m, 2H), 7.54-7.41 (m, 2H), 7.35-7.28 (m, 1H), 3.84 (s,3H), 3.56-3.47 (m, 4H).  45

F LC-MS: m/z 305.2 (M + H⁺); ¹H NMR (CDCl₃): δ 8.81 (s, 1H), 8.12-8.09(m, 1H), 7.97-7.94 (m, 1H), 7.79-7.72 (m, 2H), 7.40 (d, J = 1.4 Hz, 1H),7.04- 6.97 (m, 2H), 6.47 (dd, ¹J = 3.4 Hz, ²J = 1.2 Hz, 1H), 3.84 (s,3H), 3.76-3.72 (m, 2H), 3.62-3.57 (m, 2H).  46

F LC-MS: m/z 321.1 (M + H⁺); ¹H NMR (CDCl₃): δ 8.83 (s, 1H), 8.11-8.03(m, 2H), 7.79-7.70 (m, 2H), 7.54 (s, 1H), 7.33-7.31 (m, 2H), 6.94 (s,1H), 3.63- 3.59 (m, 5H), 3.35-3.30 (m, 2H).  47

F LC-MS: m/z 316.4 (M + H⁺); ¹H NMR (CDCl₃): δ 8.86 (s, 1H), 8.57-8.55(m, 2H), 8.12-8.03 (m, 2H), 7.80-7.70 (m, 2H), 7.76-7.59 (m, 2H), 7.28(s, 1H), 3.65-3.59 (m, 5H), 3.37-3.32 (m, 2H).  48

F LC-MS: m/z 333.3 (M + H⁺); ¹H NMR (CDCl₃): δ 8.87 (s, 1H), 8.17-8.04(m, 3H), 7.80-7.70 (m, 2H), 7.27-7.25 (m, 1H), 7.21-7.16 (m, 2H),7.10-7.03 (m, 1H), 3.65-3.58 (m, 5H), 3.37-3.31 (m, 2H).  49

F LC-MS: m/z 333.4 (M + H⁺); ¹H NMR (CDCl₃): δ. 8.85 (s, 1H), 8.12-8.03(m, 3H), 7.80-7.70 (m, 2H), 7.51-7.42 (m, 2H), 7.35-7.29 (m, 1H), 7.07(s, 1H), 6.90 (t, J = 8.4 Hz, 1H), 3.65-3.60 (m, 5H), 3.36 (t, J = 14.9Hz, 1H).  50

F LC-MS: m/z 351.4 (M + H⁺); ¹H NMR (CDCl₃): δ 8.86 (s, 1H), 8.11-8.03(m, 2H), 7.90-7.85 (m, 1H), 7.75 (t, J = 7.4 Hz, 3H), 7.14-7.07 (m, 1H),7.01- 6.95 (m, 1H), 3.65-3.58 (m, 5H), 3.34 (t, J = 14.7 Hz, 2H).  51

F LC-MS m/z 316.4 (M + H⁺).  52

G-1 MS (ESI) m/z 307 (M + H⁺); ¹H NMR (400 MHz, CD₃OD): δ 8.21-8.17 (m,1H), 7.81-7.79 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.54-7.49 (m, 1H),7.46 (t, J = 0.8 Hz, 1H), 7.20 (s, 1H), 6.57 (d, J = 3.2 Hz, 1H),6.48-6.46 (m, 1H), 3.26 (t, J = 2.0 Hz, 2H), 3.13 (t, J = 2.0 Hz, 2H). 53

G-1 MS (ESI) m/z 357 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 8.09-8.08(m, 2H), 7.76-7.74 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.54-7.45 (m, 2H),7.42-7.34 (m, 3H), 3.44 (t, J = 2.0 Hz, 2H), 3.23 (t, J = 2.0 Hz, 2H). 54

G-1 MS (ESI) m/z 351 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 8.09 (d, J =8.0 Hz, 1H), 7.80-7.74 (m, 3H), 7.62- 7.60 (d, J = 8.0 Hz, 1H), 7.56 (s,1H), 7.47 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 3.16-3.13 (m,2H), 3.09- 3.05 (m, 2H).  55

G-1 MS (ESI) m/z 367.1 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 8.12- 8.05(m, 3H), 7.90 (s, 1H), 7.54-7.49 (m, 1H), 7.86-7.77 (m, 1H), 7.65-7.59(m, 3H), 7.56-7.48 (m, 2H), 7.45-7.41 (m, 1H), 3.49 (t, J = 6.8 Hz, 2H),3.26 (t, J = 6.8 Hz, 2H).  56

G-1 MS (ESI) m/z 331.4 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 12.58 (s,1H), 11.93 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.78 (q, J = 7.4 Hz, 1H),7.62-7.45 (m, 5H), 7.21 (q, J = 7.4 Hz, 1H), 6.98 (d, J = 6.8 Hz, 1H),3.15 (q, J = 6.6 Hz, 2H), 3.08 (q, J = 6.8 Hz, 2H), 2.31 (s, 3H).  57

G-2 MS (ESI) m/z 318.1 (M + H⁺); ¹H NMR (400 MHz, CD₃OD): δ 8.47 (d, J =6.0 Hz, 2H), 8.19 (t, J = 13.6 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.75(d, J = 5.2 Hz, 2H), 7.68 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H),3.30 (t, J = 7.6 Hz, 2H), 3.17 (t, J = 7.6 Hz, 2H).  58

G-2 MS (ESI) m/z 368 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 9.00-8.98(m, 1H), 8.55-8.52 (m, 1H), 8.38 (s, 1H), 8.25-8.23 (m, 1H), 8.11 (t, J= 8.0 Hz, 2H), 7.80-7.74 (m, 2H), 7.70 (dd, ¹J = 8.4 Hz, ²J = 4.4 Hz,1H), 7.54 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 3.55 (t, J =6.8 Hz, 2H), 3.27 (t, J = 6.8 Hz, 2H).  59

G-2 MS (ESI) m/z 335.1 (M + H⁺); ¹H NMR (400 MHz, CD₃OD): δ 8.07 (dd, ¹J= 7.6 Hz, ²J = 0.8 Hz, 1H), 7.69- 7.63 (m, 3H), 7.47 (d, J = 8.0 Hz,1H), 7.42-7.38 (m, 2H), 7.28-7.20 (m, 2H), 3.48 (t, J = 6.8 Hz, 2H),3.21 (t, J = 6.8 Hz, 2H).  60

G-2 MS (ESI) m/z 335.1 (M + H⁺); ¹H NMR (400 MHz, CD₃OD): δ 8.17 (dd, ¹J= 8.0 Hz, ²J = 0.4 Hz, 1H), 7.79- 7.72 (m, 4H), 7.57 (d, J = 7.6 Hz,1H), 7.51-7.47 (m, 1H), 7.29-7.24 (m, 2H), 3.57 (t, J = 6.8 Hz, 2H),3.30 (t, J = 6.8 Hz, 2H).  61

G-2 MS (ESI) m/z 335.1 (M + H⁺); ¹H NMR (400 MHz, CD₃OD): δ 8.18 (dd, ¹J= 8.0 Hz, ²J = 1.2 Hz, 1H), 7.79- 7.77 (m, 1H), 7.64-7.61 (m, 2H), 7.54-7.51 (m, 2H), 7.49-7.45 (m, 2H), 7.09- 7.08 (m, 1H), 3.44 (t, J = 7.2Hz, 2H), 3.24 (t, J = 7.2 Hz, 2H).  62

G-2 MS (ESI) m/z 385.1 (M + H⁺); ¹H NMR (400 MHz, CD₃OD): δ 8.19 (dd, ¹J= 8.0 Hz, ²J = 1.2 Hz, 1H), 7.92- 7.89 (m, 1H), 7.81-7.74 (m, 3H), 7.62-7.50 (m, 4H), 3.58 (t, J = 6.8 Hz, 2H), 3.33-3.30 (t, J = 6.8 Hz, 2H). 63

G-2 MS (ESI) m/z 393.2 (M + H⁺); ¹H NMR (400 MHz, CD₃OD): δ 8.19 (dd, ¹J= 8.0 Hz, ²J = 1.2 Hz, 1H), 7.82 (s, 1H), 7.80-7.75 (m, 5H), 7.69-7.66(m, 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.52- 7.45 (m, 3H), 7.41-7.38 (m,1H), 3.59 (t, J = 7.2 Hz, 2H), 3.34 (t, J = 7.2 Hz, 2H).  64

G-1 MS (ESI) m/z 323 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 12.58 (s,1H), 11.97 (s, 1H), 8.10 (d, J = 7.2 Hz, 1H), 7.78 (t, J = 7.2 Hz, 1H),7.61 (d, J = 8.0 Hz, 1H), 7.56-7.50 (m, 2H), 7.47 (t, J = 6.8 Hz, 1H),7.41 (d, J = 0.8 Hz, 1H), 7.29 (brs, 1H), 3.19-3.10 (m, 2H), 3.10-3.04(m, 2H).  65

G-1 MS (ESI) m/z 361 (M + H⁺); ¹H NMR (400 MHz, CD₃OD): δ 8.09 (d, J =8.0 Hz, 1H), 7.80-7.76 (m, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.47 (d, J =8.0 Hz, 1H), 7.41 (s, 1H), 7.29-7.27 (m, 1H), 7.14-7.09 (m, 1H),6.88-6.85 (m, 1H), 6.00 (s, 2H), 3.15-3.10 (m, 2H), 3.08- 3.04 (m, 2H). 66

G-1 LC-MS: m/z 290.3 (M + H⁺); ¹H NMR (DMSO-d₆): δ 8.27-8.24 (m, J =8.4, 1H), 7.94 (dd, ¹J = 11.6 Hz, ²J = 8.3 Hz, 2H), 7.73 (t, J = 8.3 Hz,1H), 7.54 (d, J = 6.9 Hz, 1H), 7.22 (s, 1H), 6.48 (d, J = 4.9 Hz, 2H),3.36-3.30 (m, 2H), 3.17-3.12 (m, 2H).  67

G-1 LC-MS: m/z 306.4 (M + H⁺); ¹H NMR (DMSO-d₆): δ. 8.27-8.24 (d, J =8.5 Hz, 1H), 7.94 (dd, ¹J = 12.1 Hz, ²J = 8.3 Hz, 2H), 7.73 (t, J = 7.0Hz, 1H), 7.56-7.37 (m, 6H), 3.36-3.31 (m, 2H), 3.17-3.11 (m, 2H).  68

G-1 LC-MS: m/z 301.4 (M + H⁺); ¹H NMR (CDCl₃): δ. 8.47 (d, J = 6.2 Hz,2H), 8.27 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.91 (d, J =8.1 Hz, 1H), 7.75 (m, 3H), 7.66 (s, 1H), 7.58 (t, J = 7.0 Hz, 1H), 7.41(d, J = 8.5 Hz, 1H), 3.46-3.42 (m, 2H), 3.27-3.24 (m, 2H).  69

G-1 LC-MS: m/z 318.1 (M + H⁺); ^(!)H NMR (CD₃OD): δ. 8.25 (d, J = 8.5Hz, 1H), 8.03 (m, 1H), 7.91-7.83 (m, 2H), 7.75 (t, J = 8.4 Hz, 1H), 7.48(t, J = 8.0 Hz, 1H), 7.41-7.33 (m, 2H), 7.26-7.10 (m, 3H), 3.46-3.40 (m,2H), 3.33-3.26 (m, 2H).  70

G-1 LC-MS: m/z 318.2 (M + H⁺); ¹H NMR (CD₃OD): δ. 8.25 (d, J = 8.4 Hz,1H), 8.01 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.0, 1H), 7.75 (t, J = 8.3Hz, 1H), 7.59-7.54 (m, 1H), 7.48-7.32 (m, 5H), 6.96 (t, J = 8.5 Hz, 1H),3.44-3.39 (m, 2H), 3.33-3.25 (m, 2H).  71

G-1 LC-MS: m/z 336.4 (M + H⁺); ¹H NMR (CDCl₃): δ. 8.15 (t, J = 7.8 Hz,2H), 7.87-7.77 (m, 3H), 7.61-7.56 (m, 1H), 7.47 (d, J = 3.3 Hz, 1H),7.37 (d, J = 8.5 Hz, 1H), 7.14-7.07 (m, 1H), 7.04- 6.96 (m, 1H),3.49-3.41 (m, 4H).  72

G-1 LC-MS: m/z 291.4 (M + H⁺); ¹H NMR (CDCl₃): δ. 8.81 (s, 1H), 8.15 (d,J = 7.8 Hz, 2H), 7.87-7.77 (m, 2H), 7.40 (s, 1H), 7.17 (s, 1H), 6.60 (s,1H), 6.46 (s, 1H), 3.56-3.52 (m, 2H), 3.45- 3.41 (m, 2H).  73

G-1 LC-MS: m/z 307.1 (M + H⁺); ¹H NMR (CDCl₃): δ. 8.82 (s, 1H),8.16-8.09 (t, J = 19.0 Hz, 2H), 7.86-7.77 (m, 2H), 7.48 (s, 1H),7.34-7.33 (m, 2H), 7.11 (s, 1H), 3.57-3.53 (m, 2H), 3.46-3.42 (m, 2H). 74

G-1 LC-MS: m/z 302 (M + H⁺); ¹H NMR (CD₃OD): δ. 8.78 (s, 1H), 8.50 (t, J= 6.0 Hz, 2H), 8.06 (dd, ¹J = 6.5 Hz, ²J = 2.1 Hz, 2H), 7.85-7.78 (m,5H), 3.31-3.52 (m, 2H), 3.42-3.37 (m, 2H).  75

G-1 LC-MS: m/z 319.4 (M + H⁺); ¹H NMR (CDCl₃): δ. 8.83 (s, 1H), 8.15 (t,J = 7.9 Hz, 3H), 7.87-7.76 (m, 2H), 7.42- 7.41 (d, J = 2.5 Hz, 1H),7.21-7.10 (m, 3H), 3.58-3.54 (m, 2H), 3.49-3.45 (m, 2H).  76

G-1 LC-MS: m/z 319.2 (M + H⁺); ¹H NMR (CDCl₃): δ. 8.83 (s, 1H),8.16-8.10 (m, 2H), 7.87-7.77 (m, 2H), 7.51 (s, 2H), 7.40-7.32 (m, 1H),7.24 (s, 1H), 6.95- 6.90 (t, J = 7.4 Hz, 1H), 3.61-3.54 (m, 2H),3.47-3.43 (m, 2H).  77

G-1 LC-MS: m/z 337.1 (M + H⁺); ¹H NMR (CDCl₃): δ. 8.84 (s, 1H), 8.14 (d,J = 6.5 Hz, 2H), 7.88-7.77 (m, 3H), 7.46 (d, J = 3.2 Hz, 1H), 7.13-7.01(m, 2H), 3.58-3.54 (m, 2H), 3.49-3.45 (m, 2H).  78

G-1 LC-MS: m/z 302.4 (M + H⁺); ¹H NMR (CDCl₃): δ. 8.94 (s, 1H), 8.87 (s,1H), 8.64 (d, J = 4.3 Hz, 1H), 8.24 (dd, ¹J = 8.7 Hz, ²J = 1.7 Hz, 1H),8.10-8.06 (m, 1H), 8.00-7.97 (m, 2H), 7.85-7.80 (m, 2H), 7.65 (dd, ¹J =8.1 Hz, ²J = 5.0 Hz, 1H), 3.67 (t, J = 3.5 Hz, 3H), 3.62 (s, 1H).  79

H LC-MS: m/z 301 (M + H⁺); ¹H NMR (CDCl₃): δ 8.79 (s, 1H), 8.09 (dd, ¹J= 6.1 Hz, ²J = 2.0 Hz, 2H), 7.82-7.70 (m, 3H), 7.65 (d, J = 7.7 Hz, 2H),7.44 (t, J = 7.9 Hz, 2H), 7.29-7.24 (m, 1H), 6.26-6.25 (m, 1H),3.52-3.47 (m, 2H), 3.36-3.31 (m, 2H).  80

I LC-MS: m/z 302 (M + H⁺); ¹H NMR (CDCl₃): δ 8.78 (s, 1H), 8.13-8.07 (m,2H), 7.99-7.95 (m, 2H), 7.82-7.73 (m, 2H), 7.48-7.39 (m, 3H), 6.91 (s,1H), 3.49-3.44 (m, 2H), 3.40-3.35 (m, 2H).  81

J LC-MS: m/z 312 (M + H⁺); ¹H NMR (CDCl₃):. δ 8.77 (s, 1H), 8.09 (dd, ¹J= 6.4 Hz, ²J = 2.0 Hz, 2H), 8.00-7.97 (m, 2H), 7.80-7.71 (m, 2H),7.68-7.63 (m, 1H), 7.59-7.56 (m, 1H), 7.50-7.39 (m, 3H), 7.12 (d, J =7.4 Hz, 1H), 3.65-3.60 (m, 2H), 3.50-3.45 (m, 2H).  82

K LC-MS: m/z 318 (M + H⁺); ¹H NMR (DMSO-d₆) δ. 11.63 (s, 1H), 8.48 (d, J= 7.9 Hz, 1H), 7.98 (dd, ¹J = 7.9 Hz, ²J = 1.5 Hz, 1H), 7.69 (d, J = 7.3Hz, 2H), 7.59-7.48 (m, 2H), 7.33 (t, J = 7.7 Hz, 2H), 7.19 (m, 2H),3.04-2.99 (m, 2H), 2.90-2.86 (m, 2H).  83

L-1 MS (ESI): m/z 340 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ9.43 (d, J = 8.0 Hz, 1H), 9.07-9.05 (m, 1H), 8.94 (s, 1H), 8.28 (d, J =8.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.74-7.72 (m, 1H), 7.68-7.64 (m,1H), 7.30-7.22 (m, 3H), 3.80-3.77 (m, 5H), 3.54 (t, J = 7.2 Hz, 2H).  84

L-1 MS (ESI): m/z 340 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.93- 8.89 (m, 3H), 8.08-8.02 (m, 2H), 7.94 (d, J = 8.0 Hz, 1H),7.75-7.69 (m, 2H), 7.66 (d, J = 8.0 Hz, 1H), 7.52-7.49 (m, 1H), 3.88 (s,3H), 3.75 (t, J = 7.2 Hz, 2H), 3.60 (t, J = 7.2 Hz, 2H).  85

L-1 MS (ESI): m/z 339 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.97- 8.95 (m, 1H), 8.90 (dd, ¹J = 3.2 Hz, ²J = 1.2 Hz, 1H), 8.04 (t, J= 6.8 Hz, 2H), 7.94 (d, J = 7.2 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H),7.73-7.69 (m, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.53-7.49 (m, 2H), 7.31 (d,J = 6.8 Hz, 1H), 3.80 (s, 3H), 3.68-3.64 (m, 2H), 3.61-3.58 (m, 2H).  86

L-1 MS (ESI): m/z 325 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃), δ8.90- 8.82 (m, 2H), 8.21 (t, J = 8.8 Hz, 2H), 7.94-7.82 (m, 4H), 7.61(t, J = 8.0 Hz, 1H), 7.52-7.49 (m, 1H), 7.41 (d, J = 8.4 Hz, 1H), 3.66(t, J = 4.0 Hz, 2H), 3.59 (t, J = 5.2 Hz, 2H).  87

L-1 MS (ESI): m/z 354 (M + H⁺); HCl salt; ¹H NMR (500 MHz, DMSO-d₆), δ9.49 (d, J = 8.0 Hz, 1H), 9.17 (d, J = 4.5 Hz, 1H), 8.99 (s, 1H),8.26-8.21 (m, 2H), 8.01 (dd, ¹J = 8.0 Hz, ²J = 4.5 Hz, 1H), 7.45 (d, J =7.5 Hz, 1H), 7.39 (d, J = 7.0 Hz, 1H), 3.97 (t, J = 7.0 Hz, 2H), 3.81(t, J = 7.0 Hz, 2H), 2.62 (s, 3H), 2.18 (s, 3H).  88

L-1 MS (ESI): m/z 368 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.95-8.92 (m,1H), 8.89 (dd, ¹J = 4.4 Hz, ²J = 1.6 Hz, 1H), 8.84 (s, 1H), 7.95 (d, J =8.8 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.51 (dd, ¹J = 8.0 Hz, ²J = 4.0Hz, 1H), 7.45 (d, J = 14.0 Hz, 1H), 7.43 (d, J = 4.0 Hz, 1H), 3.87 (s,3H), 3.76-3.72 (m, 2H), 3.65-3.61 (m, 2H), 2.73 (s, 3H), 2.70 (s, 3H).1D NOESY: δ 3.87 and 7.67 have NOE.  89

L-1 MS (ESI): m/z 368 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.90 (d, J =3.2 Hz, 1H), 8.84 (s, 1H), 8.70 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.8Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.49-7.44 (m, 3H), 4.23 (s, 3H),3.78-3.74 (m, 2H), 3.65- 3.61 (m, 2H), 2.73 (s, 3H), 2.71 (s, 3H). 1DNOESY: δ 8.70 and 4.23 have NOE.  90

L-1 MS (ESI): m/z 338 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.66 (d, J =8.0 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.92(d, J = 8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.72-7.68 (m, 1H),7.66-7.60 (m, 2H), 7.52-7.44 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.31 (d,J = 8.4 Hz, 1H), 3.74 (s, 3H), 3.67-3.63 (m, 2H), 3.59-3.55 (m, 2H).  91

L-1 MS (ESI): m/z 338 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.38 (d, J =8.4 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.99(d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H),7.73-7.66 (m, 2H), 7.57-7.44 (m, 3H), 7.33 (d, J = 8.4 Hz, 1H), 4.19 (s,3H), 3.70-3.66 (m, 2H), 3.61-3.57 (m, 2H).  92

L-2 LC-MS: m/z 275 (M + H⁺); HCl salt; ¹H NMR (CD₃OD): δ 8.94 (s, 1H),8.03-8.01 (m, 1H), 7.83-7.75 (m, 3H), 7.69-7.67 (m, 2H), 7.51-7.49 (m,2H), 3.78 (s, 4H).  93

L-2 MS (ESI): m/z 303.2 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ7.80 (s, 1H), 8.11 (m, 2H), 7.79 (m, 2H), 7.32 (s, 2H), 3.60 (m, 2H),3.54 (m, 2H), 2.34 (s, 6H).  94

L-2 MS (ESI): m/z 325.1 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.85 (s, 1H), 8.14 (m, 2H), 7.99 (s, 2H), 7.94 (m, 2H), 7.80 (m, 2H),7.40 (m, 2H), 3.66 (m, 4H).  95

L-2 MS (ESI): m/z 343.0 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.79 (s, 1H), 8.19 (d, J = 12.4 Hz, 2H), 7.52 (m, 2H), 7.22 (m, 2H),3.60 (m, 2H), 3.48 (m, 2H).  96

L-2 MS (ESI): m/z 335.0 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.61 (s, 1H), 7.59 (s, 2H), 7.32 (d, J = 13.2 Hz, 2H), 7.23 (m, 2H),4.09 (s, 3H), 4.06 (s, 3H), 3.54 (s, 4H).  97

L-2 MS (ESI): m/z 311.0 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.78 (s, 1H), 7.83 (m, 2H), 7.55 (m, 2H), 7.23 (m, 2H), 3.64 (m, 2H),3.56 (m, 2H).  98

L-2 MS (ESI): m/z 319.1 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.78 (s, 1H), 7.83 (m, 2H), 7.55 (m, 2H), 7.23 (m, 2H), 6.20 (s, 2H),3.64 (m, 2H), 3.56 (m, 2H).  99

L-2 MS (ESI): m/z 291.1 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.81 (s, 1H), 8.09 (m, 2H), 7.81 (m, 2H), 7.05 (m, 2H), 6.69 (d, J = 8.4Hz, 1H), 3.59 (m, 2H), 3.44 (m, 2H). 100

L-2 MS (ESI): m/z 331.2 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.81 (s, 1H), 8.12 (m, 2H), 7.81 (m, 2H), 7.50 (m, 2H), 7.31 (m, 1H),3.61 (m, 4H), 1.37 (m, 9H). 101

L-2 MS (ESI): m/z 327.0 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CD₃OD): δ8.76 (s, 1H), 8.00 (m, 2H), 7.77 (m, 2H), 7.51 (d, J = 6.8 Hz, 1H), 7.30(d, J = 11.2 Hz, 1H), 3.59 (t, J = 7.2 Hz, 2H), 3.48 (t, J = 7.2 Hz,2H). 102

L-2 MS (ESI): m/z 326.1 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.91 (m, 2H), 8.87 (s, 1H), 8.17 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.85(m, 3H), 7.52 (m, 1H), 3.68 (m, 4H). 103

L-2 MS (ESI): m/z 325.1 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.70 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.92(d, J = 8.0 Hz, 1H), 7.72 (m, 4H), 7.52 (t, J = 8.0 Hz, 1H), 7.44 (t, J= 8.0 Hz, 1H), 3.60 (m, 4H). 104

L-2 MS (ESI): m/z 343.1 (M + H⁺); HCl salt; ¹H NMR (400 MHz, CDCl₃): δ8.91 (m, 1H), 8.41 (d, J = 12.4 Hz, 1H), 8.23 (t, J = 9.2 Hz, 1H), 7.93(m, 1H), 7.58 (s, 2H), 7.23 (m, 2H), 3.70 (t, J = 6.8 Hz, 2H), 3.58 (t,J = 6.8 Hz, 2H). 105

L-2 MS (ESI): m/z 359.1 (M + H⁺); HCl salt; ¹H NMR (400 MHz, DMSO-d₆): δ12.32 (s, 1H), 9.00 (d, J = 7.6 Hz, 1H), 8.20 (m, 1H), 8.03 (m, 1H),7.80 (m, 1H), 7.45 (s, 2H), 7.11 (m, 2H), 3.60 (t, J = 6.4 Hz, 2H), 3.43(t, J = 6.4 Hz, 2H). 106

#21 LC-MS: m/z 289 (M + H⁺); ¹H NMR (CD₃OD): δ 7.96-7.92 (m, 2H), 7.72-7.68 (m, 2H), 7.51-7.49 (m, 2H), 7.18- 7.16 (m, 2H), 3.57 (s, 4H), 2.71(s, 3H). 107

M MS (ESI): m/z 276 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.86 (s, 1H),8.12-8.04 (m, 2H), 7.78-7.68 (m, 3H), 7.52-7.49 (m, 1H), 7.34-7.32 (m,2H), 3.71-3.60 (m, 4H). 108

M MS (ESI): m/z 318 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.80 (s, 1H),8.10-8.07 (m, 2H), 7.87-7.86 (m, 2H), 7.78-7.72 (m, 2H), 7.43-7.40 (m,2H), 7.34-7.31 (m, 2H), 3.69 (t, J = 5.8 Hz, 2H), 3.61 (t, J = 5.8 Hz,2H). 109

M MS (ESI): m/z 292 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 8.06 (d, J =6.0 Hz, 1H), 7.67 (m, 3H), 7.50 (d, J = 6.0 Hz, 1H), 7.41 (t, J = 5.4Hz, 1H), 7.35 (m, 2H), 3.40 (t, J = 5.7 Hz, 2H), 3.20 (t, J = 5.7 Hz,2H). 110

M MS (ESI): m/z 318 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 8.07 (d, J =5.7 Hz, 1H), 7.71 (t, J = 6.0 Hz, 1H), 7.57 (d, J = 5.7 Hz, 2H), 7.53(d, J = 6.0 Hz, 1H), 7.37 (m, 4H), 7.27 (t, J = 5.4 Hz, 1H), 3.32 (t, J= 5.6 Hz, 2H), 3.15 (t, J = 5.6 Hz, 2H). 111

M MS (ESI): m/z 394 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆): δ 8.09 (m, 1H),7.78 (m, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.53 (m, 2H), 7.47 (m, 3H), 7.36(m, 6H), 3.16 (m, 2H), 3.37 (m, 2H). 112

M MS (ESI): m/z 308 (M + H⁺), ¹H NMR (400 MHz, CDCl₃): δ 8.09 (d, J =9.2 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H),7.80-7.75 (m, 1H), 7.62-7.59 (d, J = 8.0 Hz, 1H), 7.49- 7.45 (m, 2H),7.41-7.37 (m, 1H), 3.63 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 7.2 Hz, 2H).113

M MS (ESI): m/z 318 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.10 (d, J =7.6 Hz, 1H), 7.84-7.76 (m, 3H), 7.62 (d, J = 7.6 Hz, 1H), 7.50-7.46 (m,4H), 6.86 (s, 1H), 3.34-3.32 (m, 2H), 3.10-3.06 (t, J = 8.4 Hz, 2H). 114

M MS (ESI): m/z 355 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.86 (s, 1H),8.09-8.07 (m, 1H), 8.03 (m, 1H), 7.76- 7.66 (m, 4H), 7.39-7.36 (m, 2H),7.22- 7.19 (m, 1H), 3.90 (t, J = 5.2 Hz, 2H), 3.61 (t, J = 6.0 Hz, 2H),3.29 (t, J = 6.4 Hz, 2H), 2.96 (t, J = 5.2 Hz, 2H), 1.95-1.93 (m, 2H),1.83-1.80 (m, 2H). 115

M MS (ESI): m/z 318 (M + H⁺); ¹H NMR (400 MHz, DMSO-d₆) δ 8.66-8.65 (m,2H), 8.09 (d, J = 8.0 Hz, 1H), 7.87-7.88 (m, 2H), 7.79 (t, J = 8.0 Hz,1H), 7.59 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 3.28 (t, J =6.0 Hz, 2H), 3.13 (t, J = 6.0 Hz, 2H). 116

M MS (ESI): m/z 334 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.31 (d, J =8.4 Hz, 1H), 8.01 (d, J = 7.6 Hz, 2H), 7.79-7.71 (m, 2H), 7.51-7.47 (m,3H), 7.46-7.26 (m, 2H), 3.59-3.56 (m, 2H), 3.37-3.34 (m, 2H). 117

#15 MS (ESI): m/z 292 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.81 (s, 1H),8.10-8.06 (m, 2H), 7.99-7.96 (m, 1H), 7.83-7.72 (m, 3H), 7.48-7.44 (m,1H), 7.37-7.33 (m, 1H), 3.79-3.75 (m, 2H), 3.68-3.64 (m, 2H). 118

#16 MS (ESI): m/z 287.1 (M + H⁺); ¹H NMR (400 MHz, CDCl₃): δ 8.84 (s,2H), 8.05 (m, 4H), 7.73 (m, 4H), 3.68 (s, 4H). 119

#17 MS (ESI) m/z 275.0 (M + H⁺); ¹H NMR (400 MHz, CD₃OD): δ 8.68 (s,1H), 8.23 (m, 1H), 8.00 (m, 2H), 7.75 (m, 2H), 7.53 (s, 1H), 7.42 (m,1H), 7.21 (m, 1H), 6.79 (m, 1H), 3.46 (m, 2H), 3.31 (m, 2H). 120

#18 LC-MS: m/z 303 (M + H⁺); ¹H NMR (CDCl₃): δ 8.38 (d, J = 2.6 Hz, 1H),7.99 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.70-7.56 (m, 4H),7.35- 7.20 (m, 4H), 5.58 (d, J = 2.6 Hz, 2H). 121

#20 LC-MS: m/z 302 (M + H⁺); ¹H NMR (CDCl₃): δ 8.25 (s, 1H), 7.91 (d, J= 8.1 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.67-7.62 (m, 3H), 7.46-7.42(m, 1H), 7.37-7.33 (m, 2H), 7.25-7.22 (m, 2H), 4.78 (d, J = 5.1 Hz, 2H).122

#22 ¹H NMR (CD₃OD): δ 9.18 (s, 1H), 9.04 (s, 1H), 8.07-8.02 (m, 2H),7.81- 7.78 (m, 2H), 7.73-7.71 (m, 2H), 7.33- 7.29 (m, 2H), 7.25-7.23 (m,1H), 5.65 (s, 2H). 123

#22 ¹H NMR (CD₃OD): δ 8.99-8.98 (m, 1H), 8.09-8.08 (m, 2H), 7.84-7.82(m, 2H), 7.71-7.69 (m, 1H), 7.63-7.61 (m, 1H), 7.55-7.53 (m, 1H),7.44-7.23 (m, 3H), 5.23 (d, J = 4.0 Hz, 1H), 4.91- 4.90 (m, 1H). 124

#19 LC-MS: m/z 305 (M + H⁺); ¹H NMR (CDCl₃): δ 8.56 (s, 1H), 8.00-7.98(m, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.72- 7.63 (m, 4H), 7.50 (s, 1H),7.39-7.34 (m, 2H), 7.32-7.24 (m, 1H).

Compounds 127 to 142 were prepared following the exemplary proceduresfor the synthesis of Compounds 125 and 126, except using suitablecarbaldehydes as starting materials. Unless otherwise specified, thesecompounds were prepared as a free base. Suitable salts of thesecompounds may be prepared using suitable acids and methods known tothose of skill in the art, for example, as exemplified for Compounds 125and 126.

Compound Number Structure Analytical Data 125

MS (ESI) m/z: 304.1 (M + H)⁺; HC1 salt; ¹H NMR (400 MHz, CDCl₃): δ 8.06(t, J = 9.2 Hz, 2H), 7.82 (d, J = 0.8 Hz, 1H), 7.78 (dd, ¹J = 8.0 Hz, ²J= 0.8 Hz, 1H), 7.69 (ddd, ¹J = 8.4 Hz, ²J = 7.2 Hz, ³J = 1.6 Hz, 1H),7.50 (ddd, ¹J = 8.4 Hz, ²J = 6.8 Hz, ³J = 0.8 Hz, 1H), 7.38 (d, J = 8.8Hz, 1H), 3.61-3.58 (m, 4H), 2.88 (s, 3H), 2.69 (s, 3H). 126

MS (ESI) m/z: 304.2 (M + H)⁺; HCl salt; ¹H NMR (400 MHz, DMSO-d₆): δ8.28 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.95 (t, J = 8.4 Hz, 2H), 7.73(dt, ¹J = 8.4 Hz, ²J = 0.8 Hz, 1H), 7.58-7.53 (m, 2H), 3.50-3.33 (m,4H), 2.81 (s, 3H), 2.44 (s, 3H). 127

MS (ESI) m/z: 322.1 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.06 (d, J =8.4 Hz, 1H), 7.82 (m, 1H), 7.77-7.71 (m, 2H), 7.63 (m, 1H), 7.54 (m,1H), 3.63 (m, 4H), 2.87 (s, 3H), 2.68 (s, 3H). 128

MS (ESI) m/z 332.1 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 7.99-7.98 (d, J= 7.6 Hz, 1H), 7.82 (s, 1H), 7.54-7.52 (d, J = 8.0 Hz, 1H), 7.30 (m,2H), 3.65 (m, 4H), 2.89 (s, 3 H), 2.73 (s, 3H), 2.71 (s, 3H), 2.49 (s,3H). 129

MS (ESI) m/z 340.1 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.34-8.31 (m,1H), 7.83 (s, 1H), 7.52-7.50 (d, J = 8.8 Hz, 1H), 7.30 (m, 1H), 7.09 (m,1 H), 3.67-3.58 (m, 4H), 2.88 (s, 3H), 2.69 (s, 3 H). 130

MS (ESI) m/z 354.2 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.34 (m, 1H),8.09 (m, 1H), 7.88 (m, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.69 (m, 2H),7.48 (m, 1H), 7.26 (m, 1H), 3.72 (m, 4H), 2.90 (s, 3H), 2.71 (s, 3H).131

MS (ESI) m/z 340.1 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.08-8.05 (d, J= 8.8 Hz, 1H), 7.83 (s, 1H), 7.53 (m, 1H), 7.42-7.36 (m, 2H), 3.66-3.59(m, 4H), 2.88 (s, 3H), 2.70 (s, 3H). 132

MS (ESI) m/z: 372.1 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.07 (d, J =8.4 Hz, 1H), 7.83 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.8Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 3.66 (m, 4 H), 2.89 (s, 3H), 2.70 (s,3H). 133

MS (ESI) m/z: 355.2 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.25 (dd, ¹J =4.4 Hz, ²J = 1.2 Hz, 1H), 8.28 (dd, ¹J = 8.0 Hz, ²J = 1.2 Hz, 1H), 8.19(d, J = 8.0 Hz, 1H), 7.79 (m, 3H), 7.65 (m, 2H), 3.84 (m, 2H), 3.66 (m,2H), 2.88 (s, 3H), 2.70 (s, 3H). 134

MS (ESI): m/z 305 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.82 (s, 1H),8.08-8.04 (m, 2H), 7.82 (d, J = 0.4 Hz, 1H), 7.77-7.69 (m, 2H),3.67-3.62 (m, 4H), 2.87 (s, 3H), 2.67 (s, 3H). 135

MS (ESI) m/z 333.2 (M + H)⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 8.86 (s, 1H),7.94 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H),3.57-3.50 (m, 4H), 2.72 (s, 3H), 2.61 (s, 3H), 2.58 (s, 3H), 2.46 (s,3H). 136

MS (ESI) m/z 333.2 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.93 (s, 1 H),7.97 (s, 1 H), 7.78 (d, J = 8.4 Hz, 1 H), 7.67 (d, J = 8.8 Hz, 1 H),3.54-3.49 (m, 4 H), 2.74 (s, 3 H), 2.67 (s, 3 H), 2.63 (s, 3 H), 2.48(s, 3 H). 137

MS (ESI): m/z: 359.2 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.45 (d, J =8.8 Hz, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.71(d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.75 (m, 4H), 3.60 (m,2H), 3.11 (t, J = 6.0 Hz, 2H), 2.92 (s, 3H), 2.76 (s, 3H), 2.23 (m, 2H).138

MS (ESI): m/z 305 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 9.09 (q, J = 2.0Hz, 1H), 8.17 (q, J = 2.0 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.81 (d, J= 1.2 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.46 (q, J = 4.4 Hz, 1H), 3.68(s, 4H), 2.87 (d, J = 0.8 Hz, 3H), 2.69 (s, 3H). 139

MS (ESI): m/z 305 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 9.47 (s, 1H),8.60 (d, J = 5.6 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.64(d, J = 6.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 3.66-3.63 (m, 4H), 2.89(s, 3H), 2.70 (s, 3H). 140

MS (ESI): m/z 305 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 8.92 (q, J = 1.6Hz, 1H), 8.35 (q, J = 0.8 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 7.82 (d, J= 1.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H),3.63-3.60 (m, 4H), 2.88 (s, 3H), 2.69 (s, 3H). 141

MS (ESI): m/z 356 (M + H)⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.07 (s, 1H),8.94 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.97 (s, 2H), 7.75 (s, 1H), 7.62(d, J = 8.0 Hz, 1H), 3.77 (t, J = 7.6 Hz, 2H), 3.56 (t, J = 7.6 Hz, 2H),2.81 (s, 3H), 2.61 (s, 3H). 142

MS (ESI): m/z 355 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.61 (d, J = 8.0Hz, 1H), 9.03 (d, J = 2.8 Hz, 1H), 9.14 (d, J = 8.0 Hz, 1H), 8.02 (d, J= 9.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.58 (dd, ¹J =8.4 Hz, ²J = 4.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 3.72 (s, 4H), 2.90(s, 3H), 2.71 (s, 3H).

In other embodiments, the following compounds were prepared using theabove procedures.

Compound No. Structure Analytical Data 143

MS (ESI): m/z 476 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.15 (s, 1H),8.87-8.83 (m, 2H), 8.10-8.05 (m, 2H), 7.92 (d, J = 9.2 Hz, 1H), 7.67 (d,J = 8.8 Hz, 1H), 7.47 (dd, ¹J = 8.4 Hz, ²J = 4.4 Hz, 1H), 3.91 (s, 3H),3.90 (t, J = 6.8 Hz, 2H), 3.65 (t, J = 7.2 Hz, 2H). 144

MS (ESI): m/z 370 [M + H]⁺; ¹H NMR (400 MHz, CD₃OD): δ 8.81 (d, J = 7.2Hz, 1H), 8.69 (dd, ¹J = 4.4 Hz, ²J = 1.6 Hz, 1H), 7.89 (d, J = 8.8 Hz,1H), 7.80 (d, J = 8.8 Hz, 1H), 7.66 (dd, ¹J = 8.0 Hz, ²J = 1.6 Hz, 1H),7.52- 7.48 (m, 2H), 7.43-7.40 (m, 1H), 7.28-7.26 (m, 1H), 4.00 (s, 3H),3.61 (s, 3H), 3.47-3.45 (m, 4H). 145

MS (ESI): m/z 327.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.90 (dd, ¹J =4.4 Hz, ²J = 1.6 Hz, 1H), 8.85 (s, 1H), 8.73 (dd, ¹J = 8.4 Hz, ²J = 0.8Hz, 1H), 8.09-8.05 (m, 3H), 7.84 (d, J = 9.2 Hz, 1H), 7.75-7.71 (m, 2H),7.66 (dd, ¹J = 8.8 Hz, ²J = 4.8 Hz, 1H), 3.70-3.62 (m, 4H). 146

MS (ESI): m/z 326.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.90 (dd, ¹J =4.4 Hz, ²J = 1.6 Hz, 1H), 8.77 (d, J = 8.4 Hz, 1H), 8.08-8.06 (m, 3H),7.85 (d, J = 9.6 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.71-7.65 (m, 2H),7.49 (t, J = 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 3.66- 3.56 (m, 4H).147

MS (ESI): m/z 326 [M + H]⁺; ¹H NMR (400 MHz, CD₃OD): δ. 9.04 (dd, ¹J =1.6 Hz, ²J = 1.2 Hz, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.69 (d, J = 7.2 Hz,1H), 8.25 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.89 (d, J =8.0 Hz, 1H), 7.79 (dd, ¹J = 4.8 Hz, ²J = 4.4 Hz, 1H), 7.75- 7.71 (m,1H), 7.57-7.49 (m, 3H), 3.62-3.31 (m, 4H). 148

MS (ESI): m/z 376 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.06 (s, 1H),8.87 (m, 2H), 7.94 (d, J = 10.0 Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.50(m, 1H), 7.32 (m, 2H), 3.96 (s, 3H), 3.87 (d, J = 7.2 Hz, 2H), 3.64 (d,J = 6.4 Hz, 2H). 149

MS (ESI): m/z 409 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.08 (s, 1H),8.89-8.87 (m, 2H), 7.94-7.92 (d, J = 8.8 Hz, 1H), 7.77-7.71 (dd, ¹J =14.8 Hz, ²J = 6.8 Hz, 2H), 7.67-7.65 (d, J = 9.2 Hz, 1H), 7.51-7.48 (m,1H), 3.93 (s, 3H), 3.90-3.87 (m, 2H), 3.69-3.66 (m, 2H). 150

MS (ESI): m/z 330 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.46 (t, J = 1.2Hz, 1H), 7.74- 7.69 (m, 3H), 7.64 (t, J = 1.2 Hz, 1H), 7.37- 7.34 (m,2H), 7.23-7.13 (m, 4H), 7.06 (s, 1H), 4.56 (s, 3H), 3.56-3.32 (m, 2H),3.22-3.18 (m, 2H). 151

¹H-NMR (400 MHz, CDCl₃); δ 8.05 (dd, ¹J = 7.6 Hz, ²J = 0.8 Hz, 1H), 7.94(brs, 1H), 7.77- 7.72 (m, 3H), 7.38-7.32 (m, 3H), 7.24 (t, J = 7.6 Hz,1H), 7.05 (s, 1H), 5.57 (brs, 1H), 3.48 (s, 3H), 3.35 (t, J = 7.6 Hz,2H), 3.19 (t, J = 7.6 Hz, 2H). 152

MS (ESI): m/z 341 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.71 (dd, ¹J =4.4 Hz, ²J = 2.0 Hz, 2H), 7.91 (dd, ¹J = 4.0 Hz, ²J = 2.0 Hz, 2H),7.75-7.72 (m, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.64 (dd, ¹J = 7.6 Hz, ²J =1.2 Hz, 1H), 7.34 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 12.8 Hz, 2H), 7.04(s, 1H), 3.52 (s, 3H), 3.40-3.37 (m, 2H), 3.28-3.23 (m, 2H). 153

MS (ESI): m/z 326.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.08 (d, J =2.8 Hz, 1H), 8.38 (d, J = 7.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.09(d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.77 (dd, ¹J = 8.4 Hz, ²J= 1.2 Hz, 1H), 7.72-7.65 (m, 2H), 7.50 (dt, ¹J = 8.0 Hz, ²J = 0.8 Hz,1H), 7.40 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 3.73-3.69 (m,2H), 3.63-3.59 (m, 2H). 154

MS (ESI): m/z 340 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.03 (d, J = 1.2Hz, 1H), 8.34 (s, 1H), 8.23 (d, J = 1.6 Hz, 1H), 8.06 (m, 2H), 7.72 (m,2H), 7.63 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.40 (m, 1H),3.91 (m, 5H), 3.60 (t, J = 6.0 Hz, 2H). 155

MS (ESI): m/z 339.0 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.02 (dd, ¹J =4.0 Hz, ²J = 2.0 Hz, 1H), 8.22 (dd, ¹J = 8.0 Hz, ²J = 2.0 Hz, 1H), 8.06(d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.77 (dd, ¹J = 8.0 Hz, ²J= 1.2 Hz, 1H), 7.77 (ddd, ¹J = 8.4 Hz, ²J = 6.8 Hz, ³J = 1.2 Hz, 1H),7.61 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.49 (ddd, ¹J = 8.0Hz, ²J = 6.8 Hz, ³J = 1.2 Hz, 1H), 7.40 (dd, ¹J = 8.0 Hz, ²J = 4.4 Hz,1H), 7.34 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 3.80-3.76 (m, 2H),3.61-3.57 (m, 2H). 156

MS (ESI): m/z 326 [M + H]⁺; ¹H NMR (400 MHz, CD₃OD): δ 8.97 (d, J = 3.6Hz, 1H), 8.56 (d, J = 6.8 Hz, 1H), 8.35 (d, J = 1.6 Hz, 1H), 8.22 (d, J= 8.4 Hz, 1H), 7.77 (d, J = 9.2 Hz, 2H), 7.66 (m, 1H), 7.55 (m, 3H),7.03 (td, J = 2.0 Hz, 1H), 3.59 (t, J = 8.0 Hz, 2H), 3.44 (t, J = 8.0Hz, 2H). 157

MS (ESI) m/z 327 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.07 (dd, ¹J = 4.4Hz, ²J = 1.6 Hz, 1H), 8.79 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.16 (dd,¹J = 8.0 Hz, ²J = 1.6 Hz, 1H), 8.08-8.03 (m, 2H), 7.76-7.67 (m, 2H),7.64 (dd, ¹J = 8.0 Hz, ²J = 4.4 Hz, 1H), 7.19 (d, J = 6.8 Hz, 1H),3.76-3.72 (m, 2H), 3.66-3.62 (m, 2H). 158

MS (ESI): m/z 337.1 [M + H]⁺; ¹H NMR (400 MHz, CD₃OD): δ 9.26 (d, J =2.0 Hz, 1 H), 8.83 (s, 1 H), 8.26 (d, J = 1.6 Hz, 1 H), 8.16 (d, J = 8.4Hz, 1H), 8.10-8.06 (m, 2H), 7.78- 7.70 (m, 4 H), 7.65 (dd, ¹J = 8.0 Hz,²J = 4.4 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 3.83-3.79 (m, 2H),3.73-3.69 (m, 2H). 159

MS (ESI): m/z 336 [M + H]⁺; ¹H NMR (400 MHz, CD₃OD): δ 9.14 (d, J = 3.6Hz, 1H), 8.96 (d, J = 7.6 Hz, 1H), 8.78 (d, J = 8.4 Hz, 1H,). 8.53 (d, J= 8.8 Hz, 1H), 8.17-8.07 (m, 5H), 7.97 (d, J = 7.2 Hz, 1H), 7.87 (d, J =5.2 Hz, 2H), 7.75 (t, J = 1.2 Hz, 1H), 3.91 (t, J = 7.6 Hz, 2H), 3.77(t, J = 7.2 Hz, 2H). 160

MS (ESI): m/z 369.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.03 (dd, ¹J =4.4 Hz, ²J = 1.6 Hz, 1H), 8.23 (dd, ¹J = 8.0 Hz, ²J = 2.0 Hz, 1H), 7.99(d, J = 8.4 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H),7.42-7.34 (m, 4H), 7.07 (dd, ¹J = 7.6 Hz, ²J = 1.2 Hz, 1H), 4.12 (s,3H), 3.84 (t, J = 7.4 Hz, 2H), 3.81 (s, 3H), 3.60 (t, J = 7.6 Hz, 2H).161

MS (ESI): m/z 369.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.95 (t, J =4.2 Hz, 1H), 8.89 (dd, ¹J = 4.0 Hz, ²J = 1.6 Hz, 1H), 7.99 (d, J = 8.4Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51 (dd,¹J = 8.8 Hz, ²J = 4.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.34 (t, J =7.4 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 4.08 (s, 3H), 3.79 (s, 3H), 3.72(t, J = 7.6 Hz, 2H), 3.59 (t, J = 7.2 Hz, 2H). 162

MS (ESI): m/z 366.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.25 (dd, ¹J =4.0 Hz, ²J = 1.6 Hz, 1H), 8.26 (dd, ¹J = 8.0 Hz, ²J = 2.0 Hz, 1H), 8.16(d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H), 7.77 (dd, ¹J = 12.8 Hz,²J = 8.8 Hz, 2H), 7.66-7.62 (m, 2H), 7.48-7.36 (m, 3H), 7.07 (dd, ¹J =7.2 Hz, ²J = 0.8 Hz, 1H), 4.12 (s, 3H), 3.82-3.77 (m, 2H), 3.70-3.66 (m,2H). 163

MS (ESI): m/z 340.1 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 9.21 (s, 1H),9.03 (dd, ¹J = 1.2 Hz, ²J = 4.0 Hz, 1H), 8.73 (d, J = 6.0 Hz, 1H), 8.23(dd, ¹J = 1.2 Hz, ²J = 8.0 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.86 (d, J= 8.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.51(d, J = 8.4 Hz, 1H), 7.41 (dd, ¹J = 4.0 Hz, ²J = 8.0 Hz, 1H), 3.91-3.87(m, 5H), 3.63-3.59 (m, 2H). 164

MS (ESI): m/z 368.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.01 (dd, ¹J =4.4 Hz, ²J = 1.6 Hz, 1H), 8.41 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.22(dd, ¹J = 8.4 Hz, ²J = 1.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.51 (d, J= 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.40 (dd, ¹J = 8.0 Hz, ²J = 4.0Hz, 1H), 3.87 (s, 3H), 3.85 (dd, ¹J = 5.6 Hz, ²J = 3.2 Hz, 2H), 3.63(dd, ¹J = 8.8 Hz, ²J = 6.4 Hz, 2H), 2.86 (s, 3H), 2.65 (s, 3H). 165

MS (ESI): m/z 368.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.95 (d, J =8.4 Hz, 1H), 8.91 (dd, ¹J = 4.4 Hz, ²J = 1.6 Hz, 1H), 8.43 (s, 1H), 8.29(d, J = 8.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H),7.53 (dd, ¹J = 8.4 Hz, ²J = 4.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 3.86(s, 3H), 3.72-3.63 (m, 4H), 2.89 (s, 3H), 2.64 (s, 3H). 166

MS (ESI): m/z 354.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 12.70 (s, 1H),8.90 (d, J = 3.2 Hz, 2H), 8.51 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.93(d, J = 9.2 Hz, 1H), 7.82 (s, 1H), 7.48 (d, J = 8.4 Hz, 2H), 3.71-3.63(m, 4H), 3.14 (s, 6H). 167

MS (ESI): m/z 355.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.05 (dd, ¹J =4.4 Hz, ²J = 1.6 Hz, 1H), 8.91 (d, J = 8.0 Hz, 1H), 8.50 (d, J = 7.6 Hz,1H), 8.42 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.64 (dd, ¹J = 8.0 Hz, ²J =4.8 Hz, 1H), 7.49 (dd, ¹J = 8.4 Hz, ²J = 7.6 Hz, 2H), 3.67 (s, 4H), 2.89(s, 3H), 2.65 (s, 3H). 168

MS (ESI): m/z 361 [M + H]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 8.06 (d, J =8.4 Hz, 1H), 7.97 (s, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.8Hz, 1H), 7.01 (d, J = 8.8 Hz, 1H), 6.11 (brs, 1H), 4.27 (t, J = 4.0 Hz,2H), 3.52-3.44 (m, 6H), 2.76 (s, 3H), 2.66 (s, 3H). 169

MS (ESI): m/z 353 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 8.97-8.93 (m,2H), 8.07-8.02 (m, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.73-7.69 (m, 1H),7.53-7.49 (m, 3H), 7.30 (d, J = 8.4 Hz, 1H), 3.75 (s, 3H), 3.66-3.54 (m,4H), 2.89 (s, 3H). 170

MS (ESI): m/z 353 [M + H]⁺; ¹H-NMR (400 MHz, CD₃OD): δ 8.87 (dd, ¹J =8.4 Hz, ²J = 1.2 Hz, 1H), 8.73 (dd, ¹J = 8.0 Hz, ²J = 1.6 Hz, 1H), 8.23(d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.2 Hz, 1H),7.75- 7.71 (m, 1H), 7.57-7.52 (m, 3H), 7.44 (d, J = 8.4 Hz, 1H), 4.06(s, 3H), 3.54 (s, 4H), 2.87 (s, 3H). 171

MS (ESI): m/z 390 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.23 (dd, ¹J =4.4 Hz, ²J = 2.0 Hz, 1H), 8.98 (td, ¹J = 8.4 Hz, ²J = 0.8 Hz, 1H), 8.89(dd, ¹J = 4.4 Hz, ²J = 1.6 Hz, 1H), 8.26 (dd, ¹J = 8.0 Hz, ²J = 1.6 Hz,1H), 8.11 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.76 (s, 2H),7.66-7.60 (m, 2H), 7.55-7.50 (m, 2H), 3.88 (t, J = 7.2 Hz, 2H), 3.76 (s,3H), 3.69 (t, J = 7.6 Hz, 2H). 172

MS (ESI): m/z 293.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.16 (s, 1H),7.72 (d, J = 7.6 Hz, 1H), 7.36-7.32 (m, 2H), 7.22-7.20 (m, 1H), 7.04 (s,1H), 3.55 (s, 3H), 3.34-3.30 (m, 2H), 3.21-3.17 (m, 2H), 2.51 (s, 3H),2.49 (s, 3H). 173

MS (ESI): m/z 330.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.83 (s, 1H),7.78 (d, J = 2.4 Hz, 1H), 8.09-8.03 (m, 2H), 7.97-7.95 (m, 1H),7.76-7.73 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 3.61 (s, 3H),3.62-3.58 (m, 2H), 3.34-3.30 (m, 2H), 2.55 (s, 3H). 174

MS (ESI): m/z 330.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.93 (dd, ¹J =4.0 Hz, ²J = 1.6 Hz, 1H), 8.80 (brd, J = 1.6 Hz, 1H), 8.34 (brd, J = 8.8Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.95 (dd, ¹J = 4.0 Hz, ²J = 2.8 Hz,1H), 7.63 (dd, ¹J = 8.4 Hz, ²J = 4.0 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H),7.08 (s, 1H), 7.15 (d, J = 8.4 Hz. 1H), 3.58 (s, 3H), 3.54 (t, J = 8.0Hz, 2H), 3.31 (dd, ¹J = 8.0 Hz, ²J = 6.4 Hz, 2H), 2.55 (s, 3H). 175

MS (ESI): m/z 294.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.91 (d, J =1.6 Hz, 1 H), 8.44 (dd, ¹J = 4.8 Hz, ²J = 1.6 Hz, 1H), 8.21 (s, 1H),8.08-8.05 (m, 1H), 7.30-7.28 (m, 1H), 7.12 (s, 1H), 3.58 (s, 3H),3.29-3.25 (m, 2H), 3.16-3.12 (m, 2H), 2.53 (s, 3H), 2.51 (s, 3H). 176

MS (ESI): m/z 327 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.04 (dd, ¹J =4.8 Hz, ²J = 1.6 Hz, 1H), 8.93 (dd, ¹J = 4.8 Hz, ²J = 1.6 Hz, 1H), 8.89(dd, ¹J = 8.0 Hz, ²J = 1.6 Hz, 1H), 8.48 (d, J = 7.2 Hz, 1H), 8.37-8.35(m, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.65-7.61 (m, 3H), 7.50 (d, J = 7.2Hz, 1H), 3.69-3.65 (m, 2H), 3.63-3.58 (m, 2H). 177

MS (ESI): m/z 327 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.10 (dd, ¹J =4.4 Hz, ²J = 2.0 Hz, 1H), 9.03 (dd, ¹J = 4.4 Hz, ²J = 2.0 Hz, 1H),8.92-8.89 (m, 1H), 8.49 (d, J = 7.2 Hz, 1H), 8.17 (dd, ¹J = 8.0 Hz, ²J =2.0 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 4.4 Hz, 1H), 7.50(m, 1H), 7.48 (m, 1H), 7.46 (t, J = 4.4 Hz, 1H), 3.71-3.67 (m, 4H). 178

MS (ESI): m/z 341 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.27 (s, 1H),8.85 (d, J = 7.6 Hz, 1H), 8.79 (d, J = 8.4 Hz, 1H), 8.65 (m, 2H), 7.92(m, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 3.77 (m,2H), 3.65 (m, 2H), 2.78 (s, 3H). 179

MS (ESI): m/z 341 [M + H]⁺; ¹H-NMR (400 MHz, CD₃OD): δ 8.92 (q, J = 1.6Hz, 1H), 8.75 (d, J = 8.4 Hz, 1H), 8.44 (d, J = 7.6 Hz, 1H), 8.35 (d, J= 7.6 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 1.6 Hz, 1H), 7.60(d, J = 1.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H),3.66 (m, 2H), 3.58 (m, 2H), 2.79 (s, 3H). 180

MS (ESI): m/z 341 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.03 (dd, ¹J =4.4 Hz, ²J = 1.2 Hz, 1H), 8.94 (d, J = 2.0 Hz, 1H), 8.91-8.89 (m, 1H),8.48 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 1.2 Hz,1H), 7.62 (dd, ¹J = 8.0 Hz, ²J = 4.4 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H),7.45 (d, J = 8.4 Hz, 1H), 3.67 (s, 4H), 2.54 (s, 3H). 181

MS (ESI): m/z 345 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.04 (dd, ¹J =4.4 Hz, ²J = 1.2 Hz, 1H), 8.99 (d, J = 3.2 Hz, 1H), 8.89 (dd, ¹J = 8.0Hz, ²J = 1.2 Hz, 1H), 8.48 (d, J = 7.6 Hz, 1H), 8.10 (d, J = 8.4 Hz,1H), 7.79 (dd, ¹J = 7.2 Hz, ²J = 2.8 Hz, 1H), 7.63 (dd, ¹J = 8.0 Hz, ²J= 4.4 Hz, 1H), 7.54-7.48 (m, 2H), 3.72- 3.63 (m, 4H). 182

MS (ESI): m/z 395 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.30 (d, J = 2.4Hz, 1H), 9.04 (dd, ¹J = 4.4 Hz, ²J = 1.2 Hz, 1H), 8.89 (dd, ¹J = 8.0 Hz,²J = 1.2 Hz, 1H), 8.47 (dd, ¹J = 4.4 Hz, ²J = 2.4 Hz, 2H), 8.22 (d, J =8.0 Hz, 1H), 7.65-7.61 (m, 2H), 7.50 (d, J = 7.2 Hz, 1H), 3.76-3.67 (m,4H). 183

MS (ESI): m/z 358.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.98 (d, J =2.8 Hz, 1H), 8.89 (dd, ¹J = 8.0 Hz, ²J = 1.6 Hz, 1H), 8.84 (dd, ¹J = 4.4Hz, ²J = 1.6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.6 Hz,1H), 7.76 (dd, ¹J = 7.6 Hz, ²J = 3.2 Hz, 1H), 7.51 (dd, ¹J = 8.0 Hz, ²J= 4.4 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H),3.56-3.52 (m, 2H), 3.43-3.39 (m, 2H), 2.34 (s, 3H). 184

MS (ESI): m/z 354.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.94 (d, J =2.4 Hz, 1H), 8.91 (dd, ¹J = 7.6 Hz, ²J = 1.6 Hz, 1H), 8.45 (dd, ¹J = 4.4Hz, ²J = 1.6 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 1.6 Hz,1H), 7.94 (d, J = 7.6 Hz, 1H), 7.51 (dd, ¹J = 8.4 Hz, ²J = 4.4 Hz, 1H),7.33-7.27 (m, 2H), 3.54-3.50 (m, 2H) 3.44-3.40 (m, 2H), 2.54 (s, 3H),2.34 (s, 3H). 185

MS (ESI): m/z 408.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.30 (d, J =2.8 Hz, 1H), 8.91-8.86 (m, 2H), 8.46 (d, J = 1.2 Hz, 1H), 8.15 (d, J =8.4 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.55-7.49 (m, 2H), 7.31 (d, J =7.2 Hz, 1H), 3.64-3.60 (m, 2H), 3.48-3.44 (m, 2H), 2.34 (s, 3H). 186

MS (ESI): m/z 354.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.96 (d, J =8.0 Hz, 1H), 8.91 (d, J = 4.4 Hz, 1H), 8.77 (d, J = 4.4 Hz, 1H), 8.26(d, J = 8.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H),7.58-7.50 (m, 2H), 7.44 (d, J = 4.4 Hz, 1H), 3.86 (s, 3H), 3.72-3.62 (m,4H), 2.78 (s, 3H). 187

MS (ESI): m/z 354.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.98 (d, J =7.2 Hz, 1H), 8.88 (d, J = 4.4 Hz, 1H), 8.76 (d, J = 4.4 Hz, 1H), 8.19(d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.57-7.43 (m, 3H), 7.34(d, J = 7.2 Hz, 1H), 3.53 (t, J = 8.0 Hz, 2H), 3.41 (t, J = 8.0 Hz, 1H),2.84 (s, 3H), 2.31 (s, 3H). 188

MS (ESI): m/z 327 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 9.04 (dd, ¹J =4.4 Hz, ²J = 1.6 Hz 1H), 8.87 (dd, ¹J = 8.0 Hz, ²J = 1.6 Hz, 1H), 8.83(s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.06 (dd, ¹J = 7.2 Hz, ²J = 1.6 Hz,2H), 7.77- 7.69 (m, 2H), 7.62 (dd, ¹J = 8.0 Hz, ²J = 4.4 Hz, 1H), 7.49(d, J = 7.6 Hz ,1H), 3.70-3.61 (m, 4H). 189

MS (ESI): m/z 326 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 8.94-8.89 (m,2H), 8.75 (s, 1H), 8.09-8.06 (m, 2H), 8.01 (d, J = 7.6 Hz, 1H),7.79-7.71 (m, 2H), 7.55 (dd, ¹J = 8.0 Hz, ²J = 4.4 Hz, 1H), 7.34 (s,1H), 7.29 (d, J = 7.6 Hz, 1H), 3.57 (t, J = 7.2 Hz, 2H), 3.45 (t, J =7.2 Hz, 2H). 190

MS (ESI): m/z 340 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 8.90 (d, J = 8.4Hz, 1H), 8.86 (dd, ¹J = 4.8 Hz, ²J = 1.6 Hz, 1H), 8.65 (s, 1H),8.09-8.04 (m, 2H), 7.82 (d, J = 7.6 Hz, 1H), 7.78-7.69 (m, 2H), 7.53(dd, ¹J = 8.0 Hz, ²J = 4.8 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 3.56 (t, J= 7.2 Hz, 2H), 3.39 (t, J = 7.2 Hz, 2H), 2.29 (s, 3H). 191

MS (ESI): m/z 374 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 8.96 (s, 1H),8.90-8.88 (m, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 9.2 Hz, 1H),7.83 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 8.0 Hz,1H), 7.50 (dd, ¹J = 8.4 Hz, ²J = 4.8 Hz, 1H), 3.94 (s, 3H), 3.85 (t, J =7.2 Hz, 2H), 3.68 (t, J = 7.2 Hz, 2H). 192

MS (ESI): m/z 344 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 8.83 (s, 1H),8.08-8.02 (m, 2H), 7.77-7.70 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.51 (d,J = 8.8 Hz, 1H), 3.67 (s, 3H), 3.65-3.61 (m, 2H), 3.46 (t, J = 7.2 Hz,2H), 3.32 (t, J = 5.2 Hz, 2H), 3.13 (t, J = 7.2 Hz, 2H), 2.07-2.00 (m,2H). 193

MS (ESI): m/z 318 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.93 (dd, ¹J =8.0 Hz, ²J = 0.8 Hz, 1H), 8.88 (dd, ¹J = 4.0 Hz, ²J = 1.6 Hz, 1H), 7.95(d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.49 (dd, ¹J = 8.4 Hz, ²J= 4.0 Hz, 1H), 6.86 (s, 1H), 3.92 (s, 3H), 3.57-3.49 (m, 4H), 2.43 (s,6H). 194

MS (ESI): m/z 426 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.88-8.85 (m,2H), 7.98 (d, J = 4.4 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 4.4 Hz, 1H),7.51-7.48 (m, 1H), 3.98 (s, 3H), 3.98-3.94 (m, 2H), 3.60 (t, J = 1.2 Hz,2H). 195

MS (ESI): m/z 326 [M + H]⁺. 196

MS (ESI): m/z 340 [M + H]⁺; ¹H-NMR (300 MHz, CDCl₃): δ 8.91-8.87 (m,2H), 8.06-8.01 (m, 3H), 7.54 (dd, ¹J = 8.1 Hz, ²J = 1.8 Hz, 1H),7.40-7.26 (m, 3H), 7.28-7.24 (m, 1H), 3.58-3.48 (m, 4H), 2.84 (s, 3H).197

MS (ESI): m/z 340 [M + H]⁺; ¹H-NMR (300 MHz, CDCl₃): δ 9.12 (dd, ¹J =4.2 Hz, ²J = 2.1 Hz, 1H), 8.93 (d, J = 8.4 Hz, 1H), 8.87 (dd, ¹J = 4.5Hz, ²J = 1.5 Hz, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 2.1 Hz,1H), 8.06 (d, J = 8.1 Hz, 1H), 7.87-7.45 (m, 2H), 7.38 (d, J = 8.1 Hz,1H), 7.32 (d, J = 7.5 Hz, 1H), 3.59- 3.42 (m, 4H), 2.37 (s, 3H). 198

MS (ESI): m/z 354.5 [M + H]⁺; ¹H-NMR (300 MHz, CDCl₃): δ 8.95 (d, J =8.1 Hz, 1H), 8.88 (d, J = 3.9 Hz, 1H), 8.03 (dd, ¹J = 10.5 Hz, ²J = 8.7Hz, 2H), 7.87 (d, J = 7.5 Hz, 1H), 7.55 (dd, ¹J = 8.1 Hz, ²J = 4.5 Hz,1H), 7.38-7.30 (m, 3H), 3.52-3.43 (m, 4H), 2.84 (s, 3H), 2.36 (s, 3H).199

MS (ESI): m/z 326 [M + H]⁺; ¹H-NMR (300 MHz, CDCl₃): δ 8.96-8.89 (m,2H), 8.39 (d, J = 8.4 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.02 (d, J =7.5 Hz, 1H), 7.67-7.53 (m, 3H), 7.35 (s, 1H), 7.32-7.26 (m, 2H), 3.56(m, 2H), 3.44 (m, 2H). 200

MS (ESI): m/z 340 [M + H]⁺; ¹H-NMR (300 MHz, CDCl₃): δ 8.93-8.87 (m,2H), 8.26 (d, J = 8.7 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.02 (d, J =7.5 Hz, 1H), 7.57-7.50 (m, 3H), 7.35- 7.25 (m, 2H), 3.55-3.39 (m, 4H),2.78 (s, 3H). 201

MS (ESI): m/z 340 [M+H]⁺; ¹H-NMR (300 MHz, CDCl₃): δ 8.93-8.85 (m, 3H),8.39 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 8.7 Hz, 1H), 7.84 (d, J = 7.5 Hz,1H), 7.65 (dd, ¹J = 8.4 Hz, ²J = 4.2 Hz, 1H), 7.55 (dd, ¹J = 8.1 Hz, ²J= 4.5 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 3.54(m, 2H), 3.38 (m, 2H), 2.24 (s, 3H). 202

MS (ESI): m/z 354.4 [M + H]⁺; ¹H-NMR (300 MHz, CDCl₃): δ 8.95-8.88 (m,1H), 8.88 (d, J = 3.0 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.15 (d, J =8.7 Hz, 1H), 7.83 (d, J = 7.5 Hz, 1H), 7.57-7.49 (m, 2H), 7.41 (d, J =8.7 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 3.51 (m, 2H), 3.36 (m, 2H), 2.78(s, 3H), 2.21 (s, 3H). 203

MS (ESI): m/z 340 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 9.12 (m, 1H),8.97 (brd, J = 8.0 Hz, 1H), 8.91 (m, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.12(d, J = 8.4 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H),7.55-7.48 (m, 3H), 3.95 (s, 3H), 3.79-3.70 (m, 4H). 204

MS (ESI): m/z 340.1 [M + H]⁺; ¹H-NMR (400 MHz, CD₃OD): δ 8.83 (dd, ¹J =8.4 Hz, ²J = 1.2 Hz, 1H), 8.80 (dd, ¹J = 8.4 Hz, ²J = 1.5 Hz, 1H), 8.70(dd, ¹J = 4.4 Hz, ²J = 1.6 Hz, 1H), 8.28 (brd, J = 8.4 Hz, 1H), 8.22(brd, J = 8.8 Hz, 1H), 7.85 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 9.6 Hz,1H), 7.66 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.52 (dd, ¹J =8.4 Hz, ²J = 4.4 Hz, 1H), 3.86 (s, 3H), 3.59-3.50 (m, 4H). 205

MS (ESI): m/z 318.2 [M + H]⁺; ¹H-NMR (400 MHz, CD₃OD): δ 8.81 (ddd, ¹J =8.4 Hz, ²J = 2.2 Hz, ³J = 2.0 Hz, 1H), 8.69 (dd, ¹J = 4.0 Hz, ²J = 1.6Hz, 1H), 8.05 (s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.78 (dd, ¹J = 8.8 Hz,²J = 0.8 Hz, 1H), 7.51 (dd, ¹J = 8.4 Hz, ²J = 4.4 Hz, 1H), 3.86 (s, 3H),3.42-3.20 (m, 4H), 2.40 (s, 3H), 2.32 (s, 3H). 206

MS (ESI): m/z 366.2 [M + H]⁺; ¹H-NMR (400 MHz, CD₃OD): δ 8.87 (dd, ¹J =8.0 Hz, ²J = 0.8 Hz, 1H), 8.72 (dd, ¹J= 8.4 Hz, ²J = 1.6 Hz, 1H), 8.47(brd, J = 8.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 8.0 Hz,1H), 7.81 (d, J = 9.2 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.71 (t, J =8.0 Hz, 1H), 7.57-7.52 (m, 2H), 7.26-7.22 (m, 2H), 3.73 (s, 3H), 3.48(m, 2H), 3.38 (m, 2H). 207

MS (ESI): m/z 366.1 [M + H]⁺; ¹H-NMR (400 MHz, CD₃OD): δ 8.99 (m, 1H),8.86 (dd, ¹J = 8.4 Hz, ²J = 1.6 Hz, 1H), 8.72 (dd, ¹J = 8.8 Hz, ²J = 1.6Hz, 1H), 8.41 (dd, ¹J = 4.8 Hz, ²J = 1.6 Hz, 1H), 8.15 (dt, ¹J = 8.0 Hz,²J = 1.6 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 9.2 Hz, 1H),7.73-7.65 (m, 2H), 7.53 (dd, ¹J = 8.4 Hz, ²J = 4.4 Hz, 1H), 7.28 (dd, ¹J= 8.4 Hz, ²J = 4.8 Hz, 1H), 7.22 (dd, ¹J = 7.6 Hz, ²J = 1.6 Hz, 1H),3.76 (s, 3H), 3.50 (m, 2H), 3.39 (m, 2H). 208

MS (ESI): m/z 352.1 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 8.93-8.87 (m,2H), 7.95 (dd, ¹J = 9.2 Hz, ²J = 0.4 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H),7.50 (dd, ¹J = 8.0 Hz, ²J = 4.4 Hz, 1H), 3.93 (s, 3H), 3.56-3.48 (m,4H), 2.54 (s, 6H). 209

MS (ESI): m/z 354.1 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 8.96 (dd, ¹J =8.4 Hz, ²J= 1.2 Hz, 1H), 8.89 (dd, ¹J = 4.4 Hz, ²J = 1.6 Hz, 1H), 8.05(brd, J = 8.4 Hz, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.8 Hz,1H), 7.84 (ddd, ¹J = 8.4 Hz, ²J = 6.8 Hz, ³J = 1.2 Hz, 1H), 7.70 (d, J =9.2 Hz, 1H), 7.58 (ddd, ¹J = 8.4 Hz, ²J = 7.2 Hz, ³J = 1.2 Hz, 1H), 7.52(dd, ¹J = 8.4 Hz, ²J = 4.4 Hz, 1H), 3.98 (s, 3H), 3.76 (m, 2H), 3.67 (m,2H), 2.91 (s, 3H). 210

MS (ESI): m/z 344.1 [M + H]⁺; ¹H-NMR (400 MHz, CDCl₃): δ 8.91 (brd, J =8.0 Hz, 1H), 8.87 (dd, ¹J = 4.0 Hz, ²J= 1.2 Hz, 1H), 7.93 (d, J = 9.2Hz, 1H), 7.67 (d, J = 8.8 Hz, 1H), 7.48 (dd, ¹J = 8.4 Hz, ²J = 4.4 Hz,1H), 3.90 (s, 3H), 3.57-3.49 (m, 4H), 2.94 (t, J = 7.6 Hz, 2H), 2.86 (t,J = 7.6 Hz, 2H), 2.38 (s, 3H), 2.10 (quin, J = 7.6 Hz, 2H). 211

MS (ESI): m/z 347.1 [M + H]⁺; ¹H NMR (400 MHz, CDCl₃): δ 8.80 (s, 1H),8.09-8.01 (m, 2H), 7.77-7.69 (m, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.73 (d,J = 8.8 Hz, 1H), 4.44 (m, 2H), 4.31 (m, 2H), 3.76 (d, J = 8.8 Hz, 1H),3.74 (d, J = 7.6 Hz, 1H), 3.70 (s, 3H), 3.46 (d, J = 7.6 Hz, 1H), 3.44(d, J = 9.2 Hz, 1H).

The following compounds may be made using synthetic methods as disclosedherein. Where applicable a Buchwald coupling (See, e.g., WO 2010/034500)may be used (General Method: Buch).

Compound No. Structure Method of Preparation 212

TT, AAA 213

AAA 214

TT, AAA 215

AAA 216

TT, AAA 217

AAA 218

TT, AAA 219

TT, AAA 220

TT, AAA 221

AAA 222

AAA 223

TT, AAA 224

AAA 225

AAA 226

AAA 227

AAA 228

AAA 229

AAA 230

TT, AAA 231

TT, AAA 232

XX, NN, Buch, AAA 233

XX, NN, Buch, AAA 234

XX, NN, Buch, AAA 235

TT, #18 236

TT, #18 237

TT, #18 238

II, #16 239

II, AAA 240

II, AAA 241

II, AAA 242

XX, NN 243

XX, NN, Buch, AAA 244

XX, NN, Buch, AAA 245

XX, NN, Buch, AAA 246

TT, #25 247

L1, #25 248

TT, #25 249

SS, #25 250

T 251

T, TT 252

TT 253

TT 254

SS 255

SS 256

SS 257

G 258

TT, AAA 259

TT, AAA 260

TT, AAA 261

TT, AAA 262

TT, AAA 263

TT, AAA 264

TT, AAA

C. In Vitro Pharmacology

In one embodiment, the compounds provided herein were assayed for theirability to inhibit human PDE-10A. In one embodiment, the activities ofthe compounds were determined using the Molecular Devices IMAP PDEFluorescence Polarization assay using recombinant human PDE-10 enzymeexpressed in a baculoviral system. Briefly, 10 μL of a compound (0.2nM-20 μM) was added to either a 96-well half area black plate or a384-well black plate along with 10 μL of Fluorescein-labeled cAMP/cGMPsubstrate as per manufacturer's instructions and 10 μL of PDE enzyme(activity 0.1 U). Following a 40-minute incubation at 37° C., 60 μL ofIMAP binding reagent was added. The plate was then read on a PerkinElmer Victor (480-535 nm). The data was analyzed using Prism Software(GraphPad Inc, San Diego, Calif.).

In one embodiment, the compounds provided herein were run through awhole cell PDE-10 assay to assess their abilities to elevateintracellular concentrations of cAMP after PDE-10 blockade. Briefly,intracellular cGMP levels in HEK293 cells over-expressing PDE-10A weremeasured in a cell-based assay. Cells were plated into 96-well plates ata density of 100,000 cells per well and incubated at 37° C. overnight.The following day, cells were treated with a compound provided herein infresh culture medium for 30 minutes. Sodium nitroprusside was then addedfrom a 5× stock to a final concentration of 200 μM and the cells wereincubated for 2 minutes exactly. The reaction was then stopped byaddition of 200 μL Lysis Reagent A (GE Healthcare) and the intracellularcGMP concentration was determined using a cGMP EIA kit (GE Healthcare)according to the manufacturer's instructions. Data were reported as anEC₃₀₀, which was the concentration of the test compound that elevatedintracellular cAMP concentrations 300% above the baseline levels.

IC₅₀ (kM) in PDE-10A Enzymatic Assay and EC₃₀₀ (QM) in Cell-Based Assay.

The potency of the compounds provided herein in human PDE-10 inhibitionassay (enzyme assay IC₅₀) and whole cell PDE-10 assay (EC₃₀₀) issummarized in the table below.

IC₅₀ or EC₃₀₀<0.5 μM ++++;

0.5<IC₅₀ or EC₃₀₀<1 μM +++;

1<IC₅₀ or EC₃₀₀<10 μM ++;

IC₅₀ or EC₃₀₀>10 μM +.

Compound No. PDE-10 IC₅₀ (μM) PDE-10 EC₃₀₀ (μM) 1 ++++ ++++ 2 ++++ 3++++ + 4 ++++ ++ 5 ++++ +++ 6 + 7 + 8 + ++++ 9 + 10 ++ 11 ++++ ++++ 12++++ ++ 13 ++++ 14 ++ 15 ++ 16 ++++ +++ 17 ++++ +++ 18 ++++ 19 ++++ ++++20 ++++ +++ 21 ++ 22 + 23 ++ 24 + 25 ++ 26 ++ 27 ++ 28 + 29 + 30 + + 31++ + 32 + 33 + 34 ++++ ++++ 35 + 36 ++++ ++ 37 + 38 + 39 ++++ ++++ 40++++ ++++ 41 ++ 42 ++++ ++++ 43 ++++ ++ 44 +++ 45 ++++ ++++ 46 ++++ ++++47 + 48 ++++ ++++ 49 ++++ ++++ 50 ++++ ++++ 51 ++++ ++ 52 ++++ ++++ 53++ 54 ++ 55 ++ 56 ++++ ++++ 57 ++ + 58 +++ ++ 59 ++++ ++ 60 +++ ++ 61++++ ++ 62 ++ 63 + 64 ++++ ++++ 65 ++ ++ 66 +++ 67 ++++ ++++ 68 ++ 69++++ ++ 70 ++++ ++ 71 +++ 72 ++++ ++++ 73 ++++ ++++ 74 ++ 75 ++++ ++++76 ++++ ++++ 77 ++++ ++++ 78 ++++ 79 +++ ++ 80 + 81 + 82 ++ + 83 ++ 84++++ 85 ++++ 86 ++++ 87 ++++ 88 ++++ 89 ++++ 90 ++++ 91 ++ 92 ++++ + 93++ 94 ++++ 95 ++ 96 ++ 97 ++ 98 ++ 99 +++ 100 ++ 101 +++ 102 ++++ ++ 103++++ + 104 ++ 105 ++ 106 +++ 107 + 108 ++++ 109 + 110 + + 111 ++ 112 +113 + 114 ++++ 115 ++ 116 ++++ 117 ++ 118 ++ 119 ++ 120 ++++ ++ 121 ++122 + 123 ++++ ++ 124 ++++ ++ 125 ++++ ++++ 126 ++++ 127 ++++ 128 ++++129 +++ 130 +++ 131 ++++ 132 +++ 133 ++++ 134 ++++ ++ 135 ++++ 136 ++++137 ++++ 138 ++++ 139 ++ 140 ++++ 141 ++++ 142 ++++ ++++ 143 ++++ 144++++ ++ 145 +++ + 146 ++++ ++++ 147 ++++ 148 ++++ 149 ++++ ++++ 150 ++151 + 152 ++ 153 ++++ 154 ++++ 155 ++++ +++ 156 ++++ 157 ++++ 158 ++++159 ++++ 160 +++ 161 ++++ 162 ++ 163 ++++ 164 ++++ 165 ++++ 166 ++++ 167++++ 168 ++ 169 + 170 ++++ 171 ++++ 172 ++++ 173 + 174 +++ 175 ++ 176++++ 177 +++ 178 179 180 ++++ 181 ++++ 182 + 183 ++++ 184 ++++ 185 +++186 ++++ 187 ++++ 188 ++++ 189 ++++ 190 ++++ 191 ++++ 192 ++++ 193 ++++++++ 194 ++++ 195 ++ 196 +++ 197 ++++ 198 +++ 199 ++++ 200 ++++ 201 ++++202 ++++ ++++ 203 ++++ 204 ++++ ++++ 205 ++++ 206 +++ 207 ++ 208 ++++++++ 209 ++++ 210 ++++ ++++ 211 ++++ ++++

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the disclosure and are encompassedby the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein by reference in their entireties.Citation or identification of any reference in this application is notan admission that such reference is available as prior art to thisapplication. The full scope of the disclosure is better understood withreference to the appended claims.

What is claimed:
 1. A compound of formula (I):A-L-B   (I), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein L is —C(R⁶)₂—C(R⁶)₂— or —(CH₂)_(u)—; A is

B is

-A¹-A²- is —CR⁸═CR⁸—; A³ is N; A⁴ is NR⁵, O, or S; A⁵ is CR⁵ or N; A⁶ isN; R¹ and R² together with the carbon atoms to which they are attachedform a 1,2-phenylene ring optionally substituted with one or more R¹¹;R³ and R⁴ are each independently (i) hydrogen, cyano, or halogen; or(ii) (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₁-C₁₀) alkoxy,(C₁-C₁₀)aminoalkyl, (C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10membered)aryl, (5 to 10 membered)heteroaryl, (3 to 12membered)heterocyclyl, hydroxy, amino, imino, amido, or thiol, each ofwhich is optionally substituted with one or more R¹¹; or (iii) R³ and R⁴together with the atoms to which they are attached form a ringoptionally substituted with one or more R¹¹; R⁵ is (i) hydrogen, cyano,or halogen; or (ii) (C₂-C₁₀)alkenyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)aminoalkyl,(C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10 membered)aryl, (5 to10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxy, amino,imino, amido, or thiol, each of which is optionally substituted with oneor more R¹¹; or (iii) R⁴ and R⁵ together with the atoms to which theyare attached form a ring optionally substituted with one or more R¹¹;R¹⁹ is (i) hydrogen, cyano, or halogen; or (ii) (C₁-C₁₀)alkyl,(C₂-C₁₀)alkenyl, (C₁-C₁₀)alkoxy, (C₁-C₁₀)aminoalkyl,(C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10 membered)aryl, (5 to10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxy, amino,imino, amido, or thiol, each of which is optionally substituted with oneor more R¹¹; R²⁰ is (i) hydrogen; or (ii) (C₁-C₁₀)alkyl,(C₂-C₁₀)alkenyl, (C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10membered)aryl, (5 to 10 membered)heteroaryl or (3 to 12membered)heterocyclyl, each of which is optionally substituted with oneor more R¹¹; each occurrence of R⁶ is independently hydrogen, halogen,or (C₁-C₆)alkyl optionally substituted with one or more halogen; eachoccurrence of R⁸ is independently (i) hydrogen, cyano, or halogen; or(ii) (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₁-C₁₀) alkoxy,(C₁-C₁₀)aminoalkyl, (C₁-C₁₀)heteroalkyl, (C₃-C₁₀)cycloalkyl, (6 to 10membered)aryl, (5 to 10 membered)heteroaryl, (3 to 12 membered)heterocyclyl, hydroxy, amino, imino, amido, or thiol, each of which isoptionally substituted with one or more R¹¹; each occurrence of R¹¹ isindependently halogen, cyano, —OR¹³, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴,—C(O)R¹³, —C(O)OR¹³, —OC(O)OR¹³, —SR¹³, —S(O)R¹³, —S(O)₂R¹³,—S(O)₂NR¹³R¹⁴, (C₁-C₁₀)alkyl optionally substituted with one or moreR¹², (C₁-C₁₀)heteroalkyl optionally substituted with one or more R¹²,(C₃-C₁₀)cycloalkyl optionally substituted with one or more R¹²,(C₇-C₁₂)aralkyl optionally substituted with one or more R¹²,(C₃-C₁₂)heteroaralkyl optionally substituted with one or more R¹², (6 to10 membered)aryl optionally substituted with one or more R¹², (5 to 10membered)heteroaryl optionally substituted with one or more R¹², or (3to 12 membered)heterocyclyl optionally substituted with one or more R¹²;each occurrence of R¹² is independently (C₁-C₆)alkyl optionallysubstituted with one or more R¹³, (C₃-C₆)cycloalkyl optionallysubstituted with one or more R¹³, halogen, cyano, ═O, —OR¹³, —NR¹³R¹⁴,—N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³, —SR¹³,—S(O)R¹³, —S(O)₂R¹³, or —S(O)₂NR¹³R¹⁴; each occurrence of R¹³ and R¹⁴ isindependently hydrogen, (C₁-C₆)alkyl, (C₁-C₆)heteroalkyl,(C₃-C₆)cycloakyl, (C₇-C₁₀)aralkyl; (C₃-C₁₂)heteroaralkyl, (6 to 10membered)aryl, (5 to 10 membered)heteroaryl, or (3 to 12membered)heterocyclyl; or R¹³ and R¹⁴ together may form a 3 to 10membered ring; and u
 3. 2. The compound of claim 1, or apharmaceutically acceptable salt or stereoisomer thereof, wherein thecompound has formula (I-A):


3. The compound of claim 2, wherein

and k is 0, 1, 2, 3, or
 4. 4. The compound of claim 3, wherein R³ is (i)hydrogen; or (ii) (C₁-C₁₀)alkyl, (6 to 10 membered)aryl, or (5 to 10membered)heteroaryl, each of which is optionally substituted with one ormore R¹¹.
 5. The compound of claim 3, wherein R⁴ is (i) hydrogen; or(ii) (C₁-C₁₀)alkyl, (6 to 10 membered)aryl, or (5 to 10membered)heteroaryl, each of which is optionally substituted with one ormore R¹¹.
 6. The compound of claim 3, wherein R⁵ is (i) hydrogen; or(ii) (C₁-C₁₀)alkyl, (6 to 10 membered)aryl, or (5 to 10membered)heteroaryl, each of which is optionally substituted with one ormore R¹¹.
 7. The compound of claim 3, wherein each occurrence of R¹¹ isindependently (C₁-C₁₀)alkyl, (6 to 10 membered)aryl or (5 to 10membered)heteroaryl, each of which is optionally substituted with one ormore R¹².
 8. The compound of claim 2, wherein A⁴ is NR⁵; and R⁵ is (i)hydrogen; or (ii) (C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, (C₁-C₁₀)heteroalkyl,(C₃-C₁₀)cycloalkyl, (6 to 10 membered) aryl, (5 to 10 membered)heteroaryl or (3 to 12 membered)heterocyclyl, each of which isoptionally substituted with one or more R¹¹; or (iii) R⁴ and R⁵ togetherwith the atoms to which they are attached form a ring optionallysubstituted with one or more R¹¹.
 9. The compound of claim 8, wherein R⁵is hydrogen or CH₃.
 10. The compound of claim 2, wherein


11. The compound of claim 2, wherein

each occurrence of R¹⁵ is independently: (i) hydrogen, halogen, cyano,—OR¹³, —N(R¹³)C(O)R¹⁴, —C(O)NR¹³R¹⁴, —C(O)R¹³, —C(O)OR¹³, —OC(O)R¹³,—SR¹³, —S(O)R¹³, —S(O)₂R¹³, —S(O)₂NR¹³R¹⁴, (C₁-C₁₀)alkyl optionallysubstituted with one or more R¹², (C₁-C₁₀)heteroalkyl optionallysubstituted with one or more R¹², (C₃-C₁₀)cycloalkyl optionallysubstituted with one or more R¹², (C₇-C₁₂)aralkyl optionally substitutedwith one or more R¹², (C₃-C₁₂)heteroaralkyl optionally substituted withone or more R¹², (6 to 10 membered)aryl optionally substituted with oneor more R¹², (5 to 10 membered)heteroaryl optionally substituted withone or more R¹², or (3 to 12 membered)heterocyclyl optionallysubstituted with one or more R¹²; and m is 0, 1, 2, 3, or
 4. 12. Thecompound of claim 11, wherein the compound is:


13. The compound of claim 1, wherein B is

wherein each R¹¹ may be the same or different.
 14. The compound of claim1, wherein B is


15. The compound of claim 1, wherein L is —CH₂—CH₂—.
 16. The compound ofclaim 1, wherein R¹ and R² together with the carbon atoms to which theyare attached form an unsubstituted 1,2-phenylene ring.
 17. The compoundof claim 1, wherein R¹ and R² together with the carbon atoms to whichthey are attached form a 1,2-phenylene ring substituted with one or moreR¹¹.
 18. A pharmaceutical composition comprising a compound of claim 1,or a pharmaceutically acceptable salt or stereoisomer thereof, and atleast one pharmaceutically acceptable excipient, diluent, or carrier.19. The pharmaceutical composition of claim 18, wherein thepharmaceutical composition further comprises one or more additionalactive agents.
 20. A method of inhibiting phosphodiesterase-10A activityin a subject, comprising administering to a subject a therapeutically orprophylactically effective amount of a compound of claim 1, or apharmaceutically acceptable salt or stereoisomer thereof.
 21. The methodof claim 20, wherein the subject suffers from a neurological disorder, aschizophrenia-related disorder, a disease having a psychosis component,a psychotic disorder, a behavior disorder, a neurodegenerative disease,a mood disorder, a manic disorder, a movement disorder, a sleepdisorder, an addiction or an eating disorder.
 22. The method of claim20, wherein the subject suffers from schizophrenia, schizophreniaspectrum disorder, schizoaffoctive disorder, schizophreniform disorder,paraphrenia, paranoid personality disorder, schizoid personalitydisorder, schizotypal personality disorder, delusional disorder,psychosis, psychoaffective disorder, aggression, delirium, Tourette'ssyndrome, convulsion, seizure, agitation, posttraumatic stress disorder,Huntington's disease, Alzheimer's disease, Parkinson's disease,dyskinesia, dementia, bipolar disorder, anxiety, depression, majordepressive disorder, dysthymia, affective disorder, obsessive-compulsivedisorder, attention deficit disorder, attention deficit hyperactivitydisorder, vertigo, pain, sensitization accompanying neuropathic pain,fibromyalgia, migraine, cognitive impairment, cognitive deficit inAlzheimer's disease, cognitive deficit in Parkinson's disease, restlessleg syndrome, multiple sclerosis, substance abuse, substance dependency,autism, obesity, undesirable weight retention, undesirable weight gain,metabolic syndrome, diabetes, impaired glucose tolerance orhyperglycemia.
 23. The method of claim 22, wherein the schizophrenia,psychosis, psychotic disorder, depression, affective disorder, pain,cognitive impairment or diabetes is selected from the group consistingof acute schizophrenia, chronic schizophrenia, not otherwise specifiedschizophrenia, Alzheimer's psychosis, Parkinson's psychosis, excitativepsychosis, organic psychosis, not otherwise specified psychosis, briefpsychotic disorder, shared psychotic disorder, substance-inducedpsychotic disorder, psychotic disorder due to a general medicalcondition, unipolar depression, treatment resistant depression, seasonalaffective disorder, neuropathic pain, inflammatory pain, cognitiveimpairment associated with schizophrenia and non-insulin dependentdiabetes.
 24. The method of claim 20, wherein the subject suffers from acentral nervous system disorder.
 25. The method of claim 20, wherein thesubject suffers from a metabolic disorder.
 26. The method of claim 20,wherein the subject is a human.
 27. A compound of formula (I-B):D-L-E   (I-B), or a pharmaceutically acceptable salt or stereoisomerthereof, wherein L is —C(R⁶)₂—C(R⁶)₂ or —(CH₂)_(u)—; R⁶ is hydrogen; Dis

E is

each Y is independently N or CR; each Z is independently N or C, whereinat least one occurrence of Z is C; provided that D contains 1, 2, 3, or4 nitrogen ring atoms; each occurrence of R is independently hydrogen,halogen, cyano, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆)hydroxyalkyl, (6 to10 membered)aryl, or (5 to 10 membered)heteroaryl; each occurrence ofR²¹, R²², R²³, and R²⁴ is independently hydrogen, halogen, cyano,(C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)heteroalkyl,(C₁-C₆)alkoxy, (C₁-C₆)aminoalkyl, (C₁-C₆)hydroxyalkyl, CH₂CN,CH₂C(O)NH₂, (C₃-C₈)cycloalkyl, (6 to 10 membered)aryl, (5 to 10membered)heteroaryl, (3 to 12 membered)heterocyclyl, (C₇-C₁₂)aralkyl,(C₃-C₁₂)heteroaralkyl, or (C₁-C₁₀)alkyl-heterocycloalkyl; R²⁵ ishydrogen, halogen, cyano, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl,(C₁-C₆)alkoxy, (C₁-C₆)hydroxyalkyl, CH₂CN, CH₂C(O)NH₂, (C₇-C₁₂)aralkyl,or (C₁-C₁₀)alkyl-heterocycloalkyl; and u is
 3. 28. The compound of claim25, wherein D is:


29. The compound of claim 27, wherein D is:


30. The compound of claim 27, wherein L is —CH₂—CH₂—O—CH₂.
 31. Thecompound of claim 27, wherein L is —CH₂—CH₂—.
 32. The compound of claim27, wherein the compound is: